Publications by authors named "Luiz Roberto Britto"

32 Publications

Neuroplasticity induced by the retention period of a complex motor skill learning in rats.

Behav Brain Res 2021 Jul 21:113480. Epub 2021 Jul 21.

Master's and Doctoral Programs in Physical Therapy, University of the City of São Paulo, São Paulo, SP, Brazil. Electronic address:

Learning complex motor skills is an essential process in our daily lives. Moreover, it is an important aspect for the development of therapeutic strategies that refer to rehabilitation processes since motor skills previously acquired can be transferred to similar tasks (motor skill transfer) or recovered without further practice after longer delays (motor skill retention). Different acrobatic exercise (AE) training protocols induce plastic changes in areas involved in motor control and improvement in motor performance. However, the plastic mechanisms involved in the retention of a complex motor skill, essential for motor learning, are not well described. Thus, our objective was to analyze the brain plasticity mechanisms involved in motor skill retention in AE training. Motor behavior tests, and the expression of synaptophysin (SYP), synapsin-I (SYS), and early growth response protein 1 (Egr-1) in brain areas involved in motor learning were evaluated. Young male Wistar rats were randomly divided into 3 groups: sedentary (SED), AE, and AE with retention period (AER). AE training was performed three times a week for 8 weeks, with 5 rounds in the circuit. After a fifteen-day retention interval, the AER was again exposed to the acrobatic circuit. Our results revealed motor performance improvement in the AE and AER groups. In the elevated beam test, the AER group presented a lower time and greater distance, suggesting retention period is important for optimizing motor learning consolidation. Moreover, AE training promoted significant plastic changes in the expression of proteins in important areas involved in control and motor learning, some of which were maintained in the AER group. In summary, these data contribute to the understanding of neural mechanisms involved in motor learning in an animal model, and can be useful to the construction of therapeutics strategies that optimize motor learning in a rehabilitative context.
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http://dx.doi.org/10.1016/j.bbr.2021.113480DOI Listing
July 2021

Association between thyroid function and Alzheimer's disease: A systematic review.

Metab Brain Dis 2021 Jun 19. Epub 2021 Jun 19.

Laboratory of Neuronal Communication, Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo, Av. Professor Lineu Prestes, 1524 - Cidade Universitária, São Paulo, SP, Brasil, 05508900.

Alterations in metabolic parameters have been associated with an increased risk of dementia, among which thyroid function has gained great importance in Alzheimer's disease (AD) pathology in recent years. However, it remains unclear whether thyroid dysfunctions could influence and contribute to the beginning and/or progression of AD or if it results from AD. This systematic review was conducted to examine the association between thyroid hormone (TH) levels and AD. Medline, ISI Web of Science, EMBASE, Cochrane library, Scopus, Scielo, and LILACS were searched, from January 2010 to March 2020. A total of 17 articles were selected. The studies reported alterations in TH and circadian rhythm in AD patients. Behavior, cognition, cerebral blood flow, and glucose consumption were correlated with TH deficits in AD patients. Whether thyroid dysfunctions and AD have a cause-effect relationship was inconclusive, however, the literature was able to provide enough data to corroborate a relationship between TH and AD. Although further studies are needed in this field, the current systematic review provides information that could help future investigations.
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http://dx.doi.org/10.1007/s11011-021-00760-1DOI Listing
June 2021

Active lifestyle enhances protein expression profile in subjects with Lewy body pathology.

Dement Neuropsychol 2021 Jan-Mar;15(1):41-50

Laboratory of Cellular Neurobiology, Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de São Paulo - São Paulo, SP, Brazil.

Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue.

Objective: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules - MAP2) changes in postmortem brain samples of individuals with Lewy body pathology.

Methods: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated.

Results: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24).

Conclusion: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.
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http://dx.doi.org/10.1590/1980-57642021dn15-010004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049574PMC
April 2021

Involvement of substance P, osteopontin and satellite glial cells on photobiomodulation-induced antinociceptive effect in an experimental model of dentin hypersensitivity.

Lasers Med Sci 2021 Aug 15;36(6):1297-1305. Epub 2021 Jan 15.

Department of Anatomy, Laboratory of Neuromodulation of Experimental Pain, University of São Paulo, Av Lineu Prestes 2415, ICB III, São Paulo, 05508-000, Brazil.

The aim of this work was to investigate the involvement of substance P (SP), osteopontin (OPN), and satellite glial cells (SGC) on photobiomodulation-induced (PBM) antinociceptive effect in an experimental model of dentin hypersensitivity (DH). Rats ingested isotonic drink (ID, pH 2.87) for 45 consecutive days and after this period received PBM irradiation at λ660 nm or λ808 nm (1 J, 3.5 J/cm, 100 mW, 10 s, 0.028 cm, continuous wave, 3 consecutive daily sessions), and were evaluated for nociceptive behavior 24, 48, 72 h, and 14 days after laser treatments. ID ingestion induced an increase on thermal sensitivity of DH characteristics in rats that was completely reversed by PBM treatment at both 660 and 808 nm. Immunohistochemical analysis revealed increased SP expression at both dentin-pulp complex (DPC) and trigeminal ganglia (TG) of DH-rats which did not occur in PBM groups by PBM treatment. Also, the increase of glial fibrillary acidic protein (GFAP) observed in the TG of DH-rats was also reversed by PBM treatment. Finally, PBM at both 660 and 808 nm increased OPN expression in the dentin-pulp complex of DH-rats after 14 days of PBM treatment. All in all, this data demonstrates that PBM reverses nociception in a DH experimental model by inhibiting neurogenic inflammation and inducing a regenerative response.
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http://dx.doi.org/10.1007/s10103-021-03246-9DOI Listing
August 2021

Physical exercise protects against mitochondria alterations in the 6-hidroxydopamine rat model of Parkinson's disease.

Behav Brain Res 2020 06 18;387:112607. Epub 2020 Mar 18.

Laboratory of Cellular Neurobiology, Department of Physiology and Biophysics, Biomedical Science Institute, University of São Paulo, São Paulo, SP, Brazil. Electronic address:

Parkinson's disease (PD) is typicaly caractherized by loss of dopaminergic neurons, as well as the presence of mitochondrial impairments. Although physical exercise is known to promote many beneficial effects in healthy subjects, such as enhancing mitocondrial biogenesis and function, it is not clear if these effects are evident after exercise in individuals with PD. The aim of this study was to investigate the effects of two different protocol durations on motor behavior (aphomorphine and gait tests), mitochondrial biogenesis signaling (PGC-1α, NRF-1 and TFAM), structure (oxidative phosphorylation system protein levels) and respiratory chain activity (complex I) in a unilateral PD rat model. For this, male Wistar rats were injected with 6-hydroxydopamine unilaterally into the striatum and submitted to an intermitent moderate treadmill exercise for one or four weeks. In the gait test, only stride width data revealed an improvement after one week of exercise. On the other hand, after 4 weeks of the exercise protocol all gait parameters analyzed and the aphomorphine test demonstrated a recovery. Analysis of protein revealed that one week of exercise was able to prevent PGC-1α and NRF-1 expression decrease in PD animals. In addition, after four weeks of physical exercise, besides PGC-1α and NRF-1, reduction in TFAM and complex I protein levels and increased complex I activity were also prevented in PD animals. Thus, our results suggest a neuroprotective and progressive effect of intermittent treadmill exercise, which could be related to its benefits on mitochondrial biogenesis signaling and respiratory chain modulation of the dopaminergic system in PD.
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http://dx.doi.org/10.1016/j.bbr.2020.112607DOI Listing
June 2020

Impairment of PGC-1α-mediated mitochondrial biogenesis precedes mitochondrial dysfunction and Alzheimer's pathology in the 3xTg mouse model of Alzheimer's disease.

Exp Gerontol 2020 05 19;133:110882. Epub 2020 Feb 19.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Impairment of mitochondrial biogenesis and mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). However, the extent to which the impairment of mitochondrial biogenesis influences mitochondrial dysfunction at the onset and during progression of AD is still unclear. Our study demonstrated that the protein expression pattern of the transcription factor pCREB/CREB, together with the protein expression of PGC-1α, NRF1 and TFAM are all significantly reduced in early ages of 3xTg-AD mice. We also found reduced mRNA expression levels of PKAC-α, CREB, PGC-1α, NRF1, NRF2 and TFAM as early as 1 month-of-age, an age at which there was no significant Aβ oligomer deposition, suggesting that mitochondrial biogenesis is likely impaired in ages preceding the development of the AD pathology. In addition, there was a decrease in VDAC2 expression, which is related to mitochondrial content and mitochondrial function, as demonstrated by protein expression of complex IV, as well as complex II + III, and complex IV activities, at later ages in 3xTg-AD mice. These results suggest that the impairment in mitochondrial biogenesis signaling mediated by PGC-1α at early ages of the AD mice model likely resulted in mitochondrial dysfunction and manifestation of the AD pathology at later ages. Taken together, enhancing mitochondrial biogenesis may represent a potential pharmacological approach for the treatment of AD.
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http://dx.doi.org/10.1016/j.exger.2020.110882DOI Listing
May 2020

Oral treatment with royal jelly improves memory and presents neuroprotective effects on icv-STZ rat model of sporadic Alzheimer's disease.

Heliyon 2020 Feb 3;6(2):e03281. Epub 2020 Feb 3.

Laboratory of Pharmacology, Butantan Institute, Avenida Vital Brasil, 1500, cep 05503-900, São Paulo, Brazil.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function. Intracerebroventricular injection of streptozotocin (icv-STZ) has been used as an experimental model of Sporadic AD (SAD) in rodents and represents a promising tool for etiopathogenic analysis and evaluation of new therapeutic proposals for AD. The icv-STZ model shows many aspects of SAD abnormalities, resulting in decreased brain glucose and energy metabolism, cognitive impairment, oxidative stress, neuronal loss, and amyloid angiopathy. Royal jelly (RJ), a substance produced by worker honeybees of the species, has been popularly used for more than 30 years in areas related to health eating and natural medicine. Researches indicate that RJ has a several pharmacological activities, including neuroprotective and improvement of cognitive function. The objective of this study was to investigate the effects of oral treatment with royal jelly during 2 weeks in Wistar rats submitted to icv-STZ on a working memory and neuroprotection, as evaluated by neurogenesis, neurodegeneration and oxidative stress. In this study, icv-STZ injection induced deleterious effects in the hippocampus, associated with cognitive impairments, and developed marked neurodegeneration, besides the reduction of neurogenesis and increased oxidative stress. On the other hand, RJ long-term oral administration induced beneficial effects in animals injured by icv-STZ injection, increasing retention time for working spatial memory, reducing neurodegeneration and oxidative stress level and increasing the proliferation of new neurons in the hippocampus. Thus, RJ promotes beneficial effects on cognitive functions and exhibits a neuroprotective action in the STZ experimental model of SAD.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005440PMC
February 2020

Retrieval of contextual aversive memory and induction of Zenk expression in the hippocampus of pigeons.

Brain Res Bull 2019 11 2;153:341-349. Epub 2019 Oct 2.

Institute of Biology, Campinas University, Campinas, Brazil.

The hippocampus has a fundamental role in many learning and memory processes, which include the formation and retrieval of context-fear associations, as evidenced by studies in rodents and birds. The present paper has analyzed contextual memory and Zenk expression in the hippocampus of the pigeon after fear conditioning. Pigeons were trained under four conditions: with 3 tone-shock associations (Paired), with shock and tone presented randomly (Unpaired), with exposure to the experimental chamber without stimulation (Control) and with only daily handling (Naive). The testing was conducted 24 h after training. All sessions were digitally recorded. The level of freezing expressed by the Paired and Unpaired groups differed significantly from that of the control group during both training and test sessions. Pigeons from the Paired group revealed a significantly greater density of Zenk positive nuclei in the ventromedial region of the hippocampus than did the Unpaired, Control and Naive groups. These data suggest that Zenk-mediated processes of synaptic plasticity in the hippocampus are induced during the retrieval of conditioned fear memory in the pigeon.
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http://dx.doi.org/10.1016/j.brainresbull.2019.09.013DOI Listing
November 2019

Endogenous protection against the 6-OHDA model of Parkinson's disease in the Amazonian rodent Proechimys.

Neurosci Lett 2019 09 17;709:134381. Epub 2019 Jul 17.

Discipline of Neuroscience, Department of Neurology and Neurosurgery, Federal University of São Paulo Paulista Medical School, São Paulo, SP, Brazil. Electronic address:

Background: Proechimys, an epilepsy-resistant rodent from Amazon Rainforest, is a promising alternative animal model for studying neurodegenerative disorders.

Objectives: To evaluate behavioral and immunohistological changes in Proechimys after 6-OHDA-induced model of PD.

Methods: Following unilateral injections of 6-OHDA into striatum, animals were assessed for exploratory behavior using the cylinder test. Brain sections were submitted to immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1).

Results: We observed normal exploratory behavior during cylinder test in all animals. We could not detect changes in the expression of TH in both striatum and SNc, suggesting that Proechimys is resistant to dopaminergic neuronal degeneration. Glial activation was observed by an increase in Iba-1 expression in both striatum and SNc, and by an increase in GFAP expression in striatum.

Conclusions: Proechimys represents a promising animal model for studying the mechanisms underlying the susceptibility of dopaminergic neurons to degeneration induced by 6-OHDA.
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http://dx.doi.org/10.1016/j.neulet.2019.134381DOI Listing
September 2019

Retinal alterations in a pre-clinical model of an autism spectrum disorder.

Mol Autism 2019 15;10:19. Epub 2019 Apr 15.

3Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP 05508-000 Brazil.

Background: Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes.

Methods: Pregnant female mice received VPA (600 mg/kg, ) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs).

Results: Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal.

Conclusions: This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.
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http://dx.doi.org/10.1186/s13229-019-0270-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466731PMC
May 2019

Motor cortex and pain control: exploring the descending relay analgesic pathways and spinal nociceptive neurons in healthy conscious rats.

Behav Brain Funct 2019 Mar 25;15(1). Epub 2019 Mar 25.

Laboratory of Neuroscience, Hospital Sírio Libanês, São Paulo, SP, 01308-060, Brazil.

Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.
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http://dx.doi.org/10.1186/s12993-019-0156-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432755PMC
March 2019

Early postnatal tobacco smoke exposure triggers anxiety-like behavior and decreases synaptic proteins even after a long exposure-free period in mice.

Brain Res 2019 03 19;1707:99-106. Epub 2018 Nov 19.

Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000 São Paulo/SP, Brazil. Electronic address:

Although environmental tobacco smoke (ETS) is mainly associated to cardiorespiratory disease, clinical and preclinical studies have showed that ETS induces behavioral disorders and deleterious effects in the brain. Our aim was to investigate the effects of ETS during the early postnatal period on locomotor activity and anxiety and in the presynaptic proteins and brain-derived neurotrophic factor (BDNF) in distinct brain regions. BALB/c mice were exposed to ETS generated from 3R4F reference research cigarettes from the third to the fourteenth days of life. Behavioral and biochemical analyzes were performed during infancy, adolescence, and adulthood. ETS exposure induced a decrease in the locomotor activity in both female and male mice during infancy and in male mice during adolescence. Mice exposed to ETS showed lower distance traveled in the open arms of the elevated plus maze than control group. We also observed a decrease in synapsin levels in the cerebellum and striatum during infancy and adolescence, which persisted during the adulthood only in the cerebellum. Synaptophysin levels were low in all brain regions studied during the infancy, which remained reduced in the cerebellum and prefrontal cortex during adolescence and in the prefrontal cortex during adulthood. BDNF levels were reduced in the striatum and prefrontal cortex during infancy. These behavioral and biochemical data indicate that exposure to ETS during a critical development period leads to anxiety-like behavior and blunted synaptic proteins levels in different regions of the brain. More important, several of these effects were not reversed even after a long exposure-free period.
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http://dx.doi.org/10.1016/j.brainres.2018.11.022DOI Listing
March 2019

Motor improvement requires an increase in presynaptic protein expression and depends on exercise type and age.

Exp Gerontol 2018 11 21;113:18-28. Epub 2018 Sep 21.

Master's and Doctoral Programs in Physical Therapy, Universidade Cidade de São Paulo, São Paulo, SP, Brazil.

The aging process is associated with structural and functional changes in the nervous system. Considering that exercise can improve the quality of life of the elderly, the aim of this study was to evaluate the effects of exercise protocols with different motor demands on synaptic protein expression (i.e., synapsin-I and synaptophysin). Cognitive and motor brain areas and the motor performance of adult and aged animals were analyzed. Adult (7 months old) and aged (18 months old) male Wistar rats were used. Animals were divided into the following groups: treadmill exercise (TE, rhythmic motor activity), acrobatic exercise (AE, complex motor activity) and sedentary (SED, control). The animals were exposed to exercise 3 times per week for 8 weeks. The brains were collected for immunohistochemistry and immunoblotting assays. Our results showed that both types of exercise induced changes in motor performance and synaptic protein expression in adult and aged animals. However, acrobatic exercise promoted a greater number of changes, mainly in the aged animals. In addition, protein expression changes occurred in a greater number of brain areas in the aged animals than in adult animals. There were clear increases in synapsin-I expression in all areas analyzed of aged animals only after acrobatic exercises. On the other hand, synaptophysin increased in the same areas but with both types of exercise. Thus, in general, our data suggest that even at advanced ages, when the aging process is already in progress, initiating physical training may be beneficial to generate neuroplasticity that can improve motor performance.
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http://dx.doi.org/10.1016/j.exger.2018.09.013DOI Listing
November 2018

NADPH oxidase contributes to streptozotocin-induced neurodegeneration.

Neuroscience 2017 09 4;358:227-237. Epub 2017 Jul 4.

Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory. The neurodegeneration induced by AD has been linked to oxidative damage. However, little is known about the involvement of NADPH oxidase 2 (Nox2), a multisubunit enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the pathogenesis of AD. The main purpose of this study was to investigate the involvement of Nox2 in memory, in AD-related brain abnormalities, oxidative damage, inflammation and neuronal death in the hippocampus in the streptozotocin (STZ)-induced AD-like state by comparing the effects of that drug on mice lacking gp91 and wild-type (Wt) mice. Nox2 gene expression was found increased in Wt mice after STZ injection. In object recognition test, Wt mice injected with STZ presented impairment in short- and long-term memory, which was not observed following Nox2 deletion. STZ treatment induced increased phosphorylation of Tau and increased amyloid-β, apoptosis-inducing factor (AIF) and astrocyte and microglial markers expression in Wt mice but not in gp91. STZ treatment increased oxidative damage and pro-inflammatory cytokines' release in Wt mice, which was not observed in gp91 mice. Nox2 deletion had a positive effect on the IL-10 baseline production, suggesting that this cytokine might contribute to the neuroprotection mechanism against STZ-induced neurodegeneration. In summary, our data suggest that the Nox2-dependent reactive oxygen species (ROS) generation contributes to the STZ-induced AD-like state.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.050DOI Listing
September 2017

Neuropeptide expression and morphometric differences in crushed alveolar inferior nerve of rats: Effects of photobiomodulation.

Lasers Med Sci 2017 May 17;32(4):833-840. Epub 2017 Mar 17.

Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 2415, São Paulo, SP, 05508-000, Brazil.

Inferior alveolar nerve (IAN) injuries may occur during various dental routine procedures, especially in the removal of impacted lower third molars, and nerve recovery in these cases is a great challenge in dentistry. Here, the IAN crush injury model was used to assess the efficacy of photobiomodulation (PBM) in the recovery of the IAN in rats following crushing injury (a partial lesion). Rats were divided into four experimental groups: without any procedure, IAN crush injury, and IAN crush injury with PBM and sham group with PBM. Treatment was started 2 days after surgery, above the site of injury, and was performed every other day, totaling 10 sessions. Rats were irradiated with GaAs Laser (Gallium Arsenide, Laserpulse, Ibramed Brazil) emitting a wavelength of 904 nm, an output power of 70 mWpk, beam spot size at target ∼0.1 cm, a frequency of 9500 Hz, a pulse time 60 ns, and an energy density of 6 J/cm. Nerve recovery was investigated by measuring the morphometric data of the IAN using TEM and by the expression of laminin, neurofilaments (NFs), and myelin protein zero (MPZ) using Western blot analysis. We found that IAN-injured rats which received PBM had a significant improvement of IAN morphometry when compared to IAN-injured rats without PBM. In parallel, all MPZ, laminin, and NFs exhibited a decrease after PBM. The results of this study indicate that the correlation between the peripheral nerve ultrastructure and the associated protein expression shows the beneficial effects of PBM.
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http://dx.doi.org/10.1007/s10103-017-2181-2DOI Listing
May 2017

Intracerebroventricular Streptozotocin as a Model of Alzheimer's Disease: Neurochemical and Behavioral Characterization in Mice.

Neurotox Res 2017 04 2;31(3):327-333. Epub 2016 Dec 2.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor Lineu Prestes, CEP 05508-900, Sao Paulo, 1524, Brazil.

Streptozotocin has been widely used to mimic some aspects of Alzheimer's disease (AD). However, especially in mice, several characteristics involved in the streptozotocin (STZ)-induced AD pathology are not well known. The main purpose of this study was to evaluate temporally the expression of AD-related proteins, such as amyloid-β (Aβ), choline acetyltransferase (ChAT), synapsin, axonal neurofilaments, and phosphorylated Tau in the hippocampus following intracerebroventricular (icv) administration of STZ in adult mice. We also analyzed the impact of STZ on short- and long-term memory by novel object recognition test. Male mice were injected with STZ or citrate buffer, and AD-related proteins were evaluated by immunoblotting assays in the hippocampus at 7, 14, or 21 days after injection. No differences between the groups were found at 7 days. The majority of AD markers evaluated were found altered at 14 days, i.e., the STZ group showed increased amyloid-β protein and neurofilament expression, increased phosphorylation of Tau protein, and decreased synapsin expression levels compared to controls. Except for synapsin, all of these neurochemical changes were transient and did not last up to 21 days of STZ injection. Moreover, both short-term and long-term memory deficits were demonstrated after STZ treatment at 14 and 21 days after STZ treatment.
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http://dx.doi.org/10.1007/s12640-016-9684-7DOI Listing
April 2017

Beta-adrenergic blockade increases GLUT4 and improves glycemic control in insulin-treated diabetic Wistar rats.

Auton Neurosci 2015 Dec 5;193:108-16. Epub 2015 Nov 5.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Objective: Unequivocal modulation of glycemic homeostasis by chronic beta-adrenergic blockade in diabetes has never been demonstrated. This study investigates the participation of beta-adrenergic system in glycemic control and muscle glucose transporter GLUT4 expression in insulin-treated diabetic rats.

Methods: Insulin-treated diabetic Wistar (W) or spontaneously hypertensive rats (SHR) were additionally treated with propranolol, and glycemic homeostasis and expression of some target mRNAs and proteins in soleus and extensor digitorum longus (EDL) muscles were analyzed.

Results: Insulin improved glycemic control in both strains. Importantly, in W, propranolol promoted a further improvement in glycemic control, which was accompanied by decreased PKA and Tnf expression, and increased Slc2a4 and GLUT4 in EDL. Those effects were not observed in diabetic-SHR.

Discussion: Propranolol-induced decrease in beta-adrenergic activity in skeletal muscles of insulin-treated diabetic Wistar rats increases GLUT4 expression in EDL, improving glycemic control. These outcomes represent a positive effect of nonselective beta-blockade, which might be extended to autonomic neuropathy.
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http://dx.doi.org/10.1016/j.autneu.2015.10.003DOI Listing
December 2015

Enhanced nitric oxide bioavailability in coronary arteries prevents the onset of heart failure in rats with myocardial infarction.

J Mol Cell Cardiol 2015 Sep 28;86:110-20. Epub 2015 Jul 28.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil. Electronic address:

Aim: The endothelium, mainly via nitric oxide (NO) release, adjusts the coronary flow. Cardiac function is closely linked to blood flow; thus, we tested the hypothesis that NO modulation in coronary arteries could be differentially adjusted after myocardial infarction (MI) in the presence or absence of heart failure (HF).

Methods And Results: Four weeks after coronary occlusion, the infarcted rats were subdivided into rats without (MI) or with HF signs according to haemodynamic parameters. The septal coronary arteries were subsequently used to perform functional and molecular experiments. Acetylcholine (ACh)-induced relaxation was decreased in the coronary arteries following HF, whereas it was enhanced in the arteries of the MI compared with those of SHAM-operated (SO) rats. The relaxation induced by the NO donor was similar among the groups. NO production, which was evaluated by 4,5-diaminofluorescein diacetate, was reduced in the coronary arteries of the HF group and increased in the arteries with MI after ACh-induced stimulation. HF coronary arteries exhibited oxidative stress, which was evaluated via ethidium bromide-positive nuclei, whereas it was decreased in MI. To evaluate the mechanisms involved in the enhanced ACh-induced relaxation in the arteries following MI, certain septal coronary arteries were pre-incubated with L-NAME (a nonselective NO synthase (NOS) inhibitor), 7-NI (a selective neuronal NOS (nNOS) inhibitor) or LY294002 (a PI3-kinase inhibitor). L-NAME and LY294002 reduced ACh-induced relaxation in the MI and SO rats; however, these effects were greater in the MI arteries. 7-NI reduced only the ACh-relaxation in MI. In addition, the eNOS, nNOS, Akt, and superoxide dismutase isoform protein expressions were greater in the coronary arteries of the MI than in those of the SO groups.

Conclusion: Our data suggested that endothelial function was closely related to cardiac function after coronary occlusion. The coronary arteries from the HF rats exhibited reduced NO bioavailability, whereas the MI rats exhibited increased NO bioavailability because of increased eNOS/nNOS/PI3-kinase/Akt pathway and a reduction in ROS generation. These results suggest that enhanced NO modulation can prevent the onset of HF.
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http://dx.doi.org/10.1016/j.yjmcc.2015.07.017DOI Listing
September 2015

Neural mobilization promotes nerve regeneration by nerve growth factor and myelin protein zero increased after sciatic nerve injury.

Growth Factors 2015 Feb 9;33(1):8-13. Epub 2014 Dec 9.

Department of Anatomy, Laboratory of Functional Neuroanatomy of Pain, Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil .

Neurotrophins are crucial in relation to axonal regrowth and remyelination following injury; and neural mobilization (NM) is a noninvasive therapy that clinically is effective in neuropathic pain treatment, but its mechanisms remains unclear. We examined the effects of NM on the regeneration of sciatic nerve after chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted to 10 sessions of NM, starting 14 days after CCI. Then, the nerves were analyzed using transmission electron microscopy and western blot for neural growth factor (NGF) and myelin protein zero (MPZ). We observed an increase of NGF and MPZ after CCI and NM. Electron microscopy revealed that CCI-NM samples had high numbers of axons possessing myelin sheaths of normal thickness and less inter-axonal fibrosis than the CCI. These data suggest that NM is effective in facilitating nerve regeneration and NGF and MPZ are involved in this effect.
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http://dx.doi.org/10.3109/08977194.2014.953630DOI Listing
February 2015

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis.

Autops Case Rep 2013 Oct-Dec;3(4):53-62. Epub 2013 Dec 31.

Department of Genetics and Evolutionary Biology - Instituto de Biociências - Universidade de São Paulo, São Paulo/SP - Brazil.

Angiomyolipomas (AMLs) are mesenchymal neoplasms, named so because of the complex tissue composition represented by variable proportions of mature adipose tissue, smooth muscle cells, and dysmorphic blood vessels. Although AMLs may rise in different sites of the body, they are mostly observed in the kidney and liver. In the case of renal AMLs, they are described in two types: isolated AMLs and AMLs associated with tuberous sclerosis (TS). While most cases of AMLs are found incidentally during imaging examinations and are asymptomatic, others may reach huge proportions causing symptoms. Pulmonary lymphangioleiomyomatosis (LAM) is a rare benign disease characterized by cystic changes in the pulmonary parenchyma and smooth muscle proliferation, leading to a mixed picture of interstitial and obstructive disease. AML and LAM constitute major features of tuberous sclerosis complex (TSC), a multisystem autosomal dominant tumor-suppressor gene complex diagnosis. The authors report the case of a young female patient who presented a huge abdominal tumor, which at computed tomography (CT) show a fat predominance. The tumor displaced the right kidney and remaining abdominal viscera to the left. Chest CT also disclosed pulmonary lesions compatible with lymphangioleiomyomatosis. Because of sudden abdominal pain accompanied by a fall in the hemoglobin level, the patient underwent an urgent laparotomy. The excised tumor was shown to be a giant renal AML with signs of bleeding in its interior. The authors call attention to the diagnosis of AML and the huge proportions that the tumor can reach, as well as for ruling out the TSC diagnosis, once it may impose genetic counseling implications..
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http://dx.doi.org/10.4322/acr.2013.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453662PMC
December 2013

Using mass spectrometry-based peptidomics to understand the brain and disorders such as Parkinson's disease and schizophrenia.

Curr Top Med Chem 2014 ;14(3):369-81

Department of Cell Biology and Development, Av. Prof. Lineu Prestes, 1524, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo S.P. Brazil 05508-000.

The numerous efforts invested in the identification of biomarkers for neurodegenerative and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, are justified because these disorders affect several million people worldwide. Although genetic implications and the role of the environment have been shown in the progression of those disorders, together with anatomical and neurochemical characteristics, an integrated view of the biochemical pathways involved in the pathophysiology of these disorders is still being unraveled. The use of proteomic methodologies, molecular mechanisms and potential biomarker candidates for the prognosis, diagnosis and treatment of brain disorders has been discussed. Similar methodologies can be applied for the large-scale identification of peptides to characterize the brain peptidome with the aim of closing the knowledge gaps that remain. Brain cells contain a large number of peptides that play pivotal roles in cell communication. Peptidome studies have recently identified more than 800 peptides in mouse brain extracts, with half of them derived from secretory pathways. For example, several of these peptides were identified as bioactive neuropeptides that activate G-coupled receptors. In addition, intracellular peptides derived from nuclear, cytosolic and mitochondrial proteins have been identified, including the hemopressins, which act with high selectivity for the cannabinoid receptor type 1. Considering the importance of peptides in cell signaling, the present review intends to discuss the recent findings of the peptidome field, focusing on Parkinson's disease and schizophrenia. New approaches to evaluate intracellular peptide signaling at the protein-protein interaction level and the future perspectives of peptides as intracellular modulators of signal transduction are explored.
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http://dx.doi.org/10.2174/1568026613666131204120747DOI Listing
October 2014

A possible new mechanism for the control of miRNA expression in neurons.

Exp Neurol 2013 Oct 7;248:546-58. Epub 2013 Aug 7.

Núcleo de Cognição e Sistemas Complexos, Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, 09210-580 Santo André, SP, Brazil.

The control of gene expression by miRNAs has been widely investigated in different species and cell types. Following a probabilistic rather than a deterministic regimen, the action of these short nucleotide sequences on specific genes depends on intracellular concentration, which in turn reflects the balance between biosynthesis and degradation. Recent studies have described the involvement of XRN2, an exoribonuclease, in miRNA degradation and PAPD4, an atypical poly(A) polymerase, in miRNA stability. Herein, we examined the expression of XRN2 and PAPD4 in developing and adult rat hippocampi. Combining bioinformatics and real-time PCR, we demonstrated that XRN2 and PAPD4 expression is regulated by the uncorrelated action of transcription factors, resulting in distinct gene expression profiles during development. Analyses of nuclei position and nestin labeling revealed that both proteins progressively accumulated during neuronal differentiation, and that they are weakly expressed in immature neurons and absent in glial and endothelial cells. Despite the differences in subcellular localization, both genes were concurrently identified within identical neuronal subpopulations, including specific inhibitory interneurons. Thus, we cope with a singular circumstance in biology: an almost complete intersected expression of functional-opposed genes, reinforcing that their antagonistically driven actions on miRNAs "make sense" if simultaneously present at the same cells. Considering that the transcriptome in the nervous system is finely tuned to physiological processes, it was remarkable that miRNA stability-related genes were concurrently identified in neurons that play essential roles in cognitive functions such as memory and learning. In summary, this study reveals a possible new mechanism for the control of miRNA expression.
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http://dx.doi.org/10.1016/j.expneurol.2013.07.022DOI Listing
October 2013

Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats.

Behav Brain Res 2013 Sep 10;252:195-203. Epub 2013 Jun 10.

Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina, PR, Brazil.

Fluoxetine (FLX) is commonly used to treat anxiety and depressive disorders in pregnant women. Since FLX crosses the placenta and is excreted in milk, maternal treatment with this antidepressant may expose the fetus and neonate to increased levels of serotonin (5-HT). Long-term behavioral abnormalities have been reported in rodents exposed to higher levels of 5-HT during neurodevelopment. In this study we evaluated if maternal exposure to FLX during pregnancy and lactation would result in behavioral and/or stress response disruption in adolescent and adult rats. Our results indicate that exposure to FLX influenced restraint stress-induced Fos expression in the amygdala in a gender and age-specific manner. In male animals, a decreased expression was observed in the basolateral amygdala at adolescence and adulthood; whereas at adulthood, a decrease was also observed in the medial amygdala. A lack of FLX exposure effect was observed in females and also in the paraventricular nucleus of both genders. Regarding the behavioral evaluation, FLX exposure did not induce anhedonia in the sucrose preference test but decreased the latency to feed of both male and female adolescent rats evaluated in the novelty-suppressed feeding test. In conclusion, FLX exposure during pregnancy and lactation decreases acute amygdalar stress response to a psychological stressor in males (adolescents and adults) as well as influences the behavior of adolescents (males and females) in a model that evaluates anxiety and/or depressive-like behavior. Even though FLX seems to be a developmental neurotoxicant, the translation of these findings to human safe assessment remains to be determined since it is recognized that not treating a pregnant or lactating woman may also impact negatively the development of the descendants.
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http://dx.doi.org/10.1016/j.bbr.2013.05.064DOI Listing
September 2013

Blocking of connexin-mediated communication promotes neuroprotection during acute degeneration induced by mechanical trauma.

PLoS One 2012 20;7(9):e45449. Epub 2012 Sep 20.

Núcleo de Cognição e Sistemas Complexos, Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo André, São Paulo, Brazil.

Accruing evidence indicates that connexin (Cx) channels in the gap junctions (GJ) are involved in neurodegeneration after injury. However, studies using KO animal models endowed apparently contradictory results in relation to the role of coupling in neuroprotection. We analyzed the role of Cx-mediated communication in a focal lesion induced by mechanical trauma of the retina, a model that allows spatial and temporal definition of the lesion with high reproducibility, permitting visualization of the focus, penumbra and adjacent areas. Cx36 and Cx43 exhibited distinct gene expression and protein levels throughout the neurodegeneration progress. Cx36 was observed close to TUNEL-positive nuclei, revealing the presence of this protein surrounding apoptotic cells. The functional role of cell coupling was assessed employing GJ blockers and openers combined with lactate dehydrogenase (LDH) assay, a direct method for evaluating cell death/viability. Carbenoxolone (CBX), a broad-spectrum GJ blocker, reduced LDH release after 4 hours, whereas quinine, a Cx36-channel specific blocker, decreased LDH release as early as 1 hour after lesion. Furthermore, analysis of dying cell distribution confirmed that the use of GJ blockers reduced apoptosis spread. Accordingly, blockade of GJ communication during neurodegeneration with quinine, but not CBX, caused downregulation of initial and effector caspases. To summarize, we observed specific changes in Cx gene expression and protein distribution during the progress of retinal degeneration, indicating the participation of these elements in acute neurodegeneration processes. More importantly, our results revealed that direct control of GJ channels permeability may take part in reliable neuroprotection strategies aimed to rapid, fast treatment of mechanical trauma in the retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447938PMC
February 2013

Prenatal LPS exposure reduces olfactory perception in neonatal and adult rats.

Physiol Behav 2011 Sep 3;104(3):417-22. Epub 2011 May 3.

Department of Pathology, School of Veterinary Medicine, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, 05508-270, São Paulo, SP, Brazil.

Prenatal lipopolysaccharide (LPS) exposure causes reproductive, behavioral and neurochemical defects in both dams and pups. The present study evaluated male rats prenatally treated with LPS for behavioral and neurological effects related to the olfactory system, which is the main sensorial path in rodents. Pregnant Wistar rats received 100 μg/kg of LPS intraperitoneally (i.p.) on gestational day (GD) 9.5, and maternal behavior was evaluated. Pups were evaluated for (1) maternal odor preference, (2) aversion to cat odor, (3) monoamine levels and turnover in the olfactory bulb (OB) and (4) protein expression (via immunoblotting) within the OB dopaminergic system and glial cells. Results showed that prenatal LPS exposure impaired maternal preference and cat odor aversion and decreased dopamine (DA) levels in the OB. This dopaminergic impairment may have been due to defects in another brain area given that protein expression of the first enzyme in the DA biosynthetic pathway was unchanged in the OB. Moreover, there was no change in the protein expression of the DA receptors. The fact that the number of astrocytes and microglia was not increased suggests that prenatal LPS did not induce neuroinflammation in the OB. Furthermore, given that maternal care was not impaired, abnormalities in the offspring were not the result of reduced maternal care.
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http://dx.doi.org/10.1016/j.physbeh.2011.04.049DOI Listing
September 2011

Discrete retinal input to the parabrachial complex of a new-world primate, the common marmoset (Callithrix jacchus).

Neurosci Lett 2008 Oct 30;443(2):99-103. Epub 2008 Jul 30.

Laboratory of Chronobiology, Biosciences Center, Federal University of Rio Grande do Norte, 59072-970 Natal-RN, Brazil.

Traditional retinal projections target three functionally complementary systems in the brain of mammals: the primary visual system, the visuomotor integration systems and the circadian timing system. In recent years, studies in several animals have been conducted to investigate the retinal projections to these three systems, despite some evidence of additional targets. The aim of this study was to disclose a previously unknown connection between the retina and the parabrachial complex of the common marmoset, by means of the intraocular injection of cholera toxin subunit b. A few labeled retinal fibers/terminals that are detected in the medial parabrachial portion of the marmoset brain show clear varicosities, suggesting terminal fields. Although the possible role of these projections remains unknown, they may provide a modulation of the cholinergic parabrachial neurons which project to the thalamic dorsal lateral geniculate nucleus.
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http://dx.doi.org/10.1016/j.neulet.2008.07.065DOI Listing
October 2008

Neural correlates of IgE-mediated allergy.

Ann N Y Acad Sci 2006 Nov;1088:116-31

Department of Pathology, School of Veterinary Medicine, University of São Paulo, Brazil.

Although many authors have considered a direct interaction between allergic reactions and behavioral changes, supporting evidence has been elusive. In this series of studies we show that after oral or nasal ovalbumin (OVA) challenge, allergic mice present increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (CeA). Mice with food allergy display higher levels of anxiety and increased serum corticosterone levels, and allergy-activated neurons express corticotropin-releasing factor (CRF) in the PVN and CeA. OVA-allergic mice develop aversion to an antigen-containing solution, and also avoid a dark compartment previously associated with nebulized OVA. Results on brain Fos expression and behavioral data seem compatible with adaptive responses. Removal of IgE by either antibody depletion or the development of oral tolerance precluded all responses analyzed here. C-sensitive fiber destruction by neonatal capsaicin inhibited the activation in the PVN, but not in the CeA, and decreased the magnitude of food aversion. Cromolyn, a mast cell stabilizer, completely blocked Fos expression in the PVN and CeA, and precluded the development of aversion to the dark compartment associated with nebulized OVA. Employing mice that do not develop an important inflammatory infiltrate following nasal OVA challenge, we found that inflammatory cells are not required at the site of challenge in order to trigger neural or behavioral correlates of murine experimental asthma. Altogether, we have built a solid foundation for understanding neuroimmune interactions during allergic responses that may contribute to the comprehension of psychological disorders associated with allergy.
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http://dx.doi.org/10.1196/annals.1366.028DOI Listing
November 2006

Avoidance behavior and neural correlates of allergen exposure in a murine model of asthma.

Brain Behav Immun 2005 Jan;19(1):52-60

Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.

Allergic asthma is characterized by intermittent airway obstruction, inflammation, airway hyperreactivity, and increased production of IgE. The pathophysiology of asthma is well understood but little is known about its influences on brain activity and behavior. We recently described the neural correlates of food allergy and its associated modulation of behavior using an experimental model that also generates a T helper type 2 (Th2)-skewed response, with high levels of IgE. Here we show that mice allergic to ovalbumin (OVA) have an increase in the activity of the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (CeA) following a single nasal OVA challenge. Moreover, we adapted a classical passive avoidance test using an OVA aerosol as the aversive stimulus. We found that allergic mice avoid entering the dark compartment of the apparatus that had been previously associated with nebulization of the allergen, while their non-immunized controls still move into the dark side of the test box. Thus, allergic mice have increased activity in areas of the CNS commonly associated with emotionality-related behavioral responses, such as the avoidance of a context previously associated with an unpleasant or harmful situation. Moreover, our findings on the avoidance test illustrate that previous experience with an airborne allergen can modify behavior.
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http://dx.doi.org/10.1016/j.bbi.2004.02.005DOI Listing
January 2005

Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats.

J Physiol 2004 Jul 7;558(Pt 1):239-48. Epub 2004 May 7.

Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, Brazil.

In the present study, we investigated the effects of the exogenous application of tetrahydrobiopterin on the endothelium-dependent vasorelaxation and superoxide anion generation in the mesenteric microvessels of intrauterine undernourished rats. In addition, we investigated the presence of peroxynitrite in these rats by evaluation of nitrotyrosine-containing proteins, a stable end-product of peroxynitrite oxidation. For this, female pregnant Wistar rats were fed either normal or 50% of the normal intake diets during the whole gestational period. Male offspring (16 weeks of age) were studied to assess microvascular reactivity, superoxide production using a hydroethidine staining assay, nitric oxide synthase (NOS) activity and nitric oxide (NO) production. Western blot analysis was used to quantify nitrotyrosine-containing proteins and relative multiplex RT-PCR analysis for endothelial NOS (eNOS) mRNA expression. Superfusion with tetrahydrobiopterin significantly decreased superoxide generation and improved vascular function. Intrauterine malnutrition induced a decrement of NOS activity and NO production without affecting the gene expression of eNOS. However, incubation with tetrahydrobiopterin significantly improved NO production after stimulation with acetylcholine or bradykinin in intrauterine undernourished rats. The fact that the nitrotyrosine-containing proteins were increased could, at first sight, suggest that the peroxynitrite is the mediator responsible for the excessive oxidation and depletion of tetrahydrobiopterin. Our study shows that exogenous application of tetrahydrobiopterin leads to a significant improvement of endothelium-dependent vasodilatation, enhanced NO production and decreased superoxide generation in microvessels of intrauterine undernourished rats. Since we found a decrease in NOS activity without an alteration in the gene expression of eNOS, we suggest that impaired NOS-dependent responses of mesenteric arterioles are related to the impairment of tetrahydrobiopterin pathways.
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http://dx.doi.org/10.1113/jphysiol.2004.064055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1664908PMC
July 2004
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