Publications by authors named "Jean-Philippe Vit"

20 Publications

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Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents.

Brain Sci 2021 Jan 26;11(2). Epub 2021 Jan 26.

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1 rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.
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http://dx.doi.org/10.3390/brainsci11020160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911729PMC
January 2021

Color and contrast vision in mouse models of aging and Alzheimer's disease using a novel visual-stimuli four-arm maze.

Sci Rep 2021 Jan 13;11(1):1255. Epub 2021 Jan 13.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA, 90048, USA.

We introduce a novel visual-stimuli four-arm maze (ViS4M) equipped with spectrally- and intensity-controlled LED emitters and dynamic grayscale objects that relies on innate exploratory behavior to assess color and contrast vision in mice. Its application to detect visual impairments during normal aging and over the course of Alzheimer's disease (AD) is evaluated in wild-type (WT) and transgenic APP/PS1 murine models of AD (AD) across an array of irradiance, chromaticity, and contrast conditions. Substantial color and contrast-mode alternation deficits appear in AD mice at an age when hippocampal-based memory and learning is still intact. Profiling of timespan, entries and transition patterns between the different arms uncovers variable AD-associated impairments in contrast sensitivity and color discrimination, reminiscent of tritanomalous defects documented in AD patients. Transition deficits are found in aged WT mice in the absence of alternation decline. Overall, ViS4M is a versatile, controlled device to measure color and contrast-related vision in aged and diseased mice.
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http://dx.doi.org/10.1038/s41598-021-80988-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806734PMC
January 2021

Oxidative muscles have better mitochondrial homeostasis than glycolytic muscles throughout life and maintain mitochondrial function during aging.

Aging (Albany NY) 2018 11;10(11):3327-3352

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia.
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http://dx.doi.org/10.18632/aging.101643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286850PMC
November 2018

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis.

Stem Cells 2018 07 15;36(7):1122-1131. Epub 2018 Apr 15.

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1 ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF. This protected motor neurons, delayed disease pathology and extended survival of the animals. These same cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects. Together this data suggests that introducing cortical astrocytes releasing GDNF represents a novel promising approach to treating ALS. Stem Cells 2018;36:1122-1131.
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http://dx.doi.org/10.1002/stem.2825DOI Listing
July 2018

Clinical correlates to assist with chronic traumatic encephalopathy diagnosis: Insights from a novel rodent repeat concussion model.

J Trauma Acute Care Surg 2017 06;82(6):1039-1048

From the Regenerative Medicine Institute (G.M.T., A.M., L.W., P.H., N.C., O.S.), Department of Biomedical Sciences (G.M.T., J-P.V.), and Biobehavioral Research Core (J-P.V.), and Division of Trauma and Critical Care, Department of Surgery (A.K., M.Y.H., N.D., E.J.L.), Cedars-Sinai Medical Center, Los Angeles, California.

Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head injuries. Chronic traumatic encephalopathy symptoms include changes in mood, behavior, cognition, and motor function; however, CTE is currently diagnosed only postmortem. Using a rat model of recurrent traumatic brain injury (TBI), we demonstrate rodent deficits that predict the severity of CTE-like brain pathology.

Methods: Bilateral, closed-skull, mild TBI was administered once per week to 35 wild-type rats; eight rats received two injuries (2×TBI), 27 rats received five injuries (5×TBI), and 13 rats were sham controls. To determine clinical correlates for CTE diagnosis, TBI rats were separated based on the severity of rotarod deficits and classified as "mild" or "severe" and further separated into "acute," "short," and "long" based on age at euthanasia (90, 144, and 235 days, respectively). Brain atrophy, phosphorylated tau, and inflammation were assessed.

Results: All eight 2×TBI cases had mild rotarod deficiency, 11 5×TBI cases had mild deficiency, and 16 cases had severe deficiency. In one cohort of rats, tested at approximately 235 days of age, balance, rearing, and grip strength were significantly worse in the severe group relative to both sham and mild groups. At the acute time period, cortical thinning, phosphorylated tau, and inflammation were not observed in either TBI group, whereas corpus callosum thinning was observed in both TBI groups. At later time points, atrophy, tau pathology, and inflammation were increased in mild and severe TBI groups in the cortex and corpus callosum, relative to sham controls. These injury effects were exacerbated over time in the severe TBI group in the corpus callosum.

Conclusions: Our model of repeat mild TBI suggests that permanent deficits in specific motor function tests correlate with CTE-like brain pathology. Assessing balance and motor coordination over time may predict CTE diagnosis.
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http://dx.doi.org/10.1097/TA.0000000000001443DOI Listing
June 2017

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

J Trauma Acute Care Surg 2016 12;81(6):1070-1079

From the Regenerative Medicine Institute (G.M.T., A.M., L.W., P.H., O.S., C.N.S.), Department of Biomedical Sciences (J-P.V., C.N.S.), and Biobehavioral Research Core (J-P.V.), Department of Surgery, Division of Trauma and Critical Care (A.K., M.Y.H., E.J.L.), Cedars-Sinai Medical Center, Los Angeles, California; and Division of Trauma, Critical Care, Burn and Emergency Surgery (P.R.), The University of Arizona Medical Center, Tucson, Arizona.

Background: Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1 mutation ("SOD1"), a model of familial amyotrophic lateral sclerosis (ALS).

Methods: A total of 42 rats, 26 WT and 16 SOD1, were examined over a study period of 25 weeks (or endpoint). At postnatal day 60, 20 WT and 7 SOD1 rats were exposed to mild, bilateral TBI once per week for either 2 weeks (2×TBI) or 5 weeks (5×TBI) using a controlled cortical impact device. Six WT and nine SOD1 rats underwent sham injury with anesthesia alone. Twenty WT rats were euthanized at 12 weeks after first injury and six WT rats were euthanized at 25 weeks after first injury. SOD1 rats were euthanized when they reached ALS disease endpoint. Weekly body weights and behavioral assessments were performed. Tauopathy in brain tissue was analyzed using immunohistochemistry.

Results: 2XTBI injured rats initially demonstrated recovery of motor function but failed to recover to baseline within the 12-week study period. Relative to both 2XTBI and sham controls, 5XTBI rats demonstrated significant deficits that persisted over the 12-week period. SOD1 5XTBI rats reached a peak body weight earlier than sham SOD1 rats, indicating earlier onset of the ALS phenotype. Histologic examination of brain tissue revealed that, in contrast with sham controls, SOD1 and WT TBI rats demonstrated cortical and corpus collosum thinning and tauopathy, which increased over time.

Conclusions: Unlike previous models of repeat brain injury, which demonstrate only transient deficits in motor function, our concussion model of repeat, mild, bilateral TBI induced long-lasting deficits in motor function, decreased cortical thickness, shrinkage of the corpus callosum, increased brain tauopathy, and earlier onset of ALS symptoms in SOD1 rats. This model may allow for a greater understanding of the complex relationship between TBI and neurodegenerative diseases and provides a potential method for testing novel therapeutic strategies.
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http://dx.doi.org/10.1097/TA.0000000000001248DOI Listing
December 2016

Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

Exp Neurol 2016 06 29;280:41-9. Epub 2016 Mar 29.

The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population.
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http://dx.doi.org/10.1016/j.expneurol.2016.03.023DOI Listing
June 2016

Acute Traumatic Brain Injury Does Not Exacerbate Amyotrophic Lateral Sclerosis in the SOD1 (G93A) Rat Model

eNeuro 2015 May-Jun;2(3). Epub 2015 Jul 3.

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center , Los Angeles, CA 90048 ; Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA 90048.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons degenerate, leading to muscle atrophy, paralysis, and death within 3 to 5 years of onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic with unknown origin. Currently, etiological links are associated with disease onset without mechanistic understanding. Of all the putative risk factors, however, head trauma has emerged as a consistent candidate for initiating the molecular cascades of ALS. Here, we test the hypothesis that traumatic brain injury (TBI) in the SOD1 (G93A) transgenic rat model of ALS leads to early disease onset and shortened lifespan. We demonstrate, however, that a one-time acute focal injury caused by controlled cortical impact does not affect disease onset or survival. Establishing the negligible involvement of a single acute focal brain injury in an ALS rat model increases the current understanding of the disease. Critically, untangling a single focal TBI from multiple mild injuries provides a rationale for scientists and physicians to increase focus on repeat injuries to hopefully pinpoint a contributing cause of ALS.
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http://dx.doi.org/10.1523/ENEURO.0059-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586929PMC
October 2015

Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.

J Neurosci 2014 Nov;34(47):15587-600

Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, and

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1(G93A) rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1(G93A) rats through targeted delivery of AAV9-SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.
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http://dx.doi.org/10.1523/JNEUROSCI.2037-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298650PMC
November 2014

Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.

Behav Pharmacol 2011 Jun;22(3):222-7

Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA.

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.
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http://dx.doi.org/10.1097/FBP.0b013e328345f72cDOI Listing
June 2011

Can satellite glial cells be therapeutic targets for pain control?

Neuron Glia Biol 2010 Feb 22;6(1):63-71. Epub 2010 Jun 22.

Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

Satellite glial cells (SGCs) undergo phenotypic changes and divide the following injury into a peripheral nerve. Nerve injury, also elicits an immune response and several antigen-presenting cells are found in close proximity to SGCs. Silencing SCG-specific molecules involved in intercellular transport (Connexin 43) or glutamate recycling (glutamine synthase) can dramatically alter nociceptive responses of normal and nerve-injured rats. Transducing SGCs with glutamic acid decarboxylase can produce analgesia in models of trigeminal pain. Taken together these data suggest that SGCs may play a role in the genesis or maintenance of pain and open a range of new possibilities for curing neuropathic pain.
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http://dx.doi.org/10.1017/S1740925X10000098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139431PMC
February 2010

Gliopathic pain: when satellite glial cells go bad.

Neuroscientist 2009 Oct;15(5):450-63

Department of Anatomy, University of California, San Francisco, California 95143-0452, USA.

Neurons in sensory ganglia are surrounded by satellite glial cells (SGCs) that perform similar functions to the glia found in the CNS. When primary sensory neurons are injured, the surrounding SGCs undergo characteristic changes. There is good evidence that the SGCs are not just bystanders to the injury but play an active role in the initiation and maintenance of neuronal changes that underlie neuropathic pain. In this article the authors review the literature on the relationship between SGCs and nociception and present evidence that changes in SGC potassium ion buffering capacity and glutamate recycling can lead to neuropathic pain-like behavior in animal models. The role that SGCs play in the immune responses to injury is also considered. We propose the term gliopathic pain to describe those conditions in which central or peripheral glia are thought to be the principal generators of principal pain generators.
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http://dx.doi.org/10.1177/1073858409336094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852320PMC
October 2009

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia.

Mol Pain 2009 Aug 5;5:42. Epub 2009 Aug 5.

Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.

Background: Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion.

Results: Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist.

Conclusion: Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya.
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http://dx.doi.org/10.1186/1744-8069-5-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734545PMC
August 2009

Evidence for a role of connexin 43 in trigeminal pain using RNA interference in vivo.

J Neurophysiol 2008 Dec 20;100(6):3064-73. Epub 2008 Aug 20.

Department of Anatomy, University of California San Francisco, San Francisco, CA 95143-0452, USA.

The importance of glial cells in the generation and maintenance of neuropathic pain is becoming widely accepted. We examined the role of glial-specific gap junctions in nociception in the rat trigeminal ganglion in nerve-injured and -uninjured states. The connexin 43 (Cx43) gap-junction subunit was found to be confined to the satellite glial cells (SGCs) that tightly envelop primary sensory neurons in the trigeminal ganglion and we therefore used Cx43 RNA interference (RNAi) to alter gap-junction function in SGCs. Using behavioral evaluation, together with immunocytochemical and Western blot monitoring, we show that Cx43 increased in the trigeminal ganglion in rats with a chronic constriction injury (CCI) of the infraorbital nerve. Reducing Cx43 expression using RNAi in CCI rats reduced painlike behavior, whereas in non-CCI rats, reducing Cx43 expression increased painlike behavior. The degree of painlike behavior in CCI rats and intact, Cx43-silenced rats was similar. Our results support previous suggestions that increases in glial gap junctions after nerve injury increases nociceptive behavior but paradoxically the reduction of gap junctions in normal ganglia also increases nociceptive behavior, possibly a reflection of the multiple functions performed by glia.
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http://dx.doi.org/10.1152/jn.90722.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604845PMC
December 2008

Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain.

Neuron Glia Biol 2006 Nov;2(4):247-57

Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0485, USA.

Satellite glial cells (SGCs) tightly envelop the perikarya of primary sensory neurons in peripheral ganglion and are identified by their morphology and the presence of proteins not found in ganglion neurons. These SGC-unique proteins include the inwardly rectifying K(+) channel Kir4.1, the connexin-43 (Cx43) subunit of gap junctions, the purinergic receptor P2Y4 and soluble guanylate cyclase. We also present evidence that the small-conductance Ca(2+)-activated K(+) channel SK3 is present only in SGCs and that SGCs divide following nerve injury. All the above proteins are involved, either directly or indirectly, in potassium ion (K(+)) buffering and, thus, can influence the level of neuronal excitability, which, in turn, has been associated with neuropathic pain conditions. We used in vivo RNA interference to reduce the expression of Cx43 (present only in SGCs) in the rat trigeminal ganglion and show that this results in the development of spontaneous pain behavior. The pain behavior is present only when Cx43 is reduced and returns to normal when Cx43 concentrations are restored. This finding shows that perturbation of a single SGC-specific protein is sufficient to induce pain responses and demonstrates the importance of PNS glial cell activity in the pathophysiology of neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435170PMC
http://dx.doi.org/10.1017/s1740925x07000427DOI Listing
November 2006

Chronic constriction injury of the infraorbital nerve in the rat using modified syringe needle.

J Neurosci Methods 2008 Jul 22;172(1):43-7. Epub 2008 Apr 22.

Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, United States.

Here we report a method for performing a chronic constriction injury (CCI) of the infraorbital nerve (ION) in the rat as a component of a chronic pain model. The surgical approach to the ION is described together with the use of a modified dental syringe needle that simplifies placing two chromic gut ligatures around the ION. This method makes the surgical procedure easier, the nerve injury more consistent across animals and reduces secondary damage to the ION and surrounding tissue. Pain behavior testing together with immunostaining for markers of nerve injury in the spinal trigeminal nucleus show the suitability of this procedure as a model of orofacial pain.
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http://dx.doi.org/10.1016/j.jneumeth.2008.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2497464PMC
July 2008

Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury.

J Neurosci 2008 Apr;28(16):4161-71

Department of Neurosurgery and Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

Growing evidence suggests that changes in the ion buffering capacity of glial cells can give rise to neuropathic pain. In the CNS, potassium ion (K+) buffering is dependent on the glia-specific inward rectifying K+ channel Kir4.1. We recently reported that the satellite glial cells that surround primary sensory neurons located in sensory ganglia of the peripheral nervous system also express Kir4.1, whereas the neurons do not. In the present study, we show that, in the rat trigeminal ganglion, the location of the primary sensory neurons for face sensation, specific silencing of Kir4.1 using RNA interference leads to spontaneous and evoked facial pain-like behavior in freely moving rats. We also show that Kir4.1 in the trigeminal ganglion is reduced after chronic constriction injury of the infraorbital nerve. These findings suggests that neuropathic pain can result from a change in expression of a single K+ channel in peripheral glial cells, raising the possibility of targeting Kir4.1 to treat pain in general and particularly neuropathic pain that occurs in the absence of nerve injury.
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http://dx.doi.org/10.1523/JNEUROSCI.5053-07.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533133PMC
April 2008

Analgesia and hyperalgesia from CRF receptor modulation in the central nervous system of Fischer and Lewis rats.

Pain 2006 Apr 21;121(3):241-260. Epub 2006 Feb 21.

Department of Neurological Surgery and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System, Ann Arbor, MI 48109-0723, USA.

This study examines the contribution of central corticotropin-releasing factor (CRF) to pain behavior. CRF is the principal modulator of the hypothalamo-pituitary-adrenal (HPA) axis, in addition to acting on many other areas of the central nervous system. We compared nociceptive thresholds (heat and mechanical) and pain behavior in response to a sustained stimulus (formalin test) between Fischer and Lewis rats that have different HPA axis activity. Intracerebroventricular (i.c.v.) administration of CRF produced dose-dependent antinociception at a lower dose in Lewis (40 ng, paw pinch 71+/-0 g) compared to Fischer rats (200 ng, 112+/-3 g). The antinociceptive effect of CRF was mostly preserved in adrenalectomized Fischer rats. The i.c.v. administration of the CRF receptor antagonist, astressin, had a hyperalgesic effect, suggesting that CRF is tonically active. Lewis rats required higher doses of astressin (5 ng, paw pinch 51+/-1 g) to show nociceptive effects compared to Fischer rats (1 ng, 79+/-1 g). Only Lewis rats vocalized during mechanical stimulus, and this behavior was prevented by diazepam or morphine but was worsened by CRF, despite its antinociceptive property. In the formalin test, CRF and astressin had the largest effect on the interphase suggesting that they act on the endogenous pain inhibitory system. CRF also increased anxiety/fear-like behaviors in the forced swim and predator odor tests. Our results establish that central CRF is a key modulator of pain behavior and indicates that CRF effects on nociception are largely independent of its mood modulating effect as well as its control of the HPA axis.
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http://dx.doi.org/10.1016/j.pain.2005.12.024DOI Listing
April 2006

The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception.

Pain 2006 Jan 19;120(1-2):188-201. Epub 2005 Dec 19.

Department of Anatomy, University of California San Francisco, San Francisco, CA 94143-0452, USA Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA Departments of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA Departments of Neuroscience, Pharmacology and Dermatology, University of Minnesota, St. Paul, MN 55108, USA.

Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.
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http://dx.doi.org/10.1016/j.pain.2005.10.033DOI Listing
January 2006

Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis.

Oncogene 2003 Nov;22(54):8645-52

1UPR 2169 CNRS, Institut Gustave Roussy IFR 54, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.

Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.
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http://dx.doi.org/10.1038/sj.onc.1207087DOI Listing
November 2003