Publications by authors named "Chandramohan Wakade"

25 Publications

  • Page 1 of 1

Emerging urinary alpha-synuclein and miRNA biomarkers in Parkinson's disease.

Metab Brain Dis 2021 Apr 21. Epub 2021 Apr 21.

Department of Physical Therapy, College of Allied Health Sciences, Augusta University, 987 St. Sebastian Way, Augusta, GA, 30912, USA.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases after Alzheimer's disease (AD), afflicting adults above the age of sixty irrespective of gender, race, ethnicity, and social status. PD is characterized by motor dysfunctions, displaying resting tremor, rigidity, bradykinesia, and postural imbalance. Non-motor symptoms, including rapid eye movement (REM) behavior disorder, constipation, and loss of sense of smell, typically occur many years before the appearance of the PD motor symptoms that lead to a diagnosis. The loss of dopaminergic neurons in the substantia nigra, which leads to the motor symptoms seen in PD, is associated with the deposition of aggregated, misfolded α-Synuclein (α-Syn, SNCA) proteins forming Lewy Bodies. Additionally, dysregulation of miRNA (a short form of mRNA) may contribute to the developing pathophysiology in PD and other diseases such as cancer. Overexpression of α-Syn and miRNA in human samples has been found in PD, AD, and dementia. Therefore, evaluating these molecules in urine, present either in the free form or in association with extracellular vesicles of biological fluids, may lead to early biomarkers for clinical diagnosis. Collection of urine is non-invasive and thus beneficial, particularly in geriatric populations, for biomarker analysis. Considering the expression and function of α-Syn and miRNA, we predict that they can be used as early biomarkers in the diagnosis and prognosis of neurodegenerative diseases.
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http://dx.doi.org/10.1007/s11011-021-00735-2DOI Listing
April 2021

Serum Levels of Inflammatory Proteins Are Associated With Peripheral Neuropathy in a Cross-Sectional Type-1 Diabetes Cohort.

Front Immunol 2021 31;12:654233. Epub 2021 Mar 31.

Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States.

Chronic low-grade inflammation is involved in the pathogenesis of type-1 diabetes (T1D) and its complications. In this cross-section study design, we investigated association between serum levels of soluble cytokine receptors with presence of peripheral neuropathy in 694 type-1 diabetes patients. Sex, age, blood pressure, smoking, alcohol intake, HbA1c and lipid profile, presence of DPN (peripheral and autonomic), retinopathy and nephropathy was obtained from patient's chart. Measurement of soluble cytokine receptors, markers of systemic and vascular inflammation was done using multiplex immunoassays. Serum levels were elevated in in DPN patients, independent of gender, age and duration of diabetes. Crude odds ratios were significantly associated with presence of DPN for 15/22 proteins. The Odds ratio (OR) remained unchanged for sTNFRI (1.72, p=0.00001), sTNFRII (1.45, p=0.0027), sIL2Rα (1.40, p=0.0023), IGFBP6 (1.51, p=0.0032) and CRP (1.47, p=0.0046) after adjusting for confounding variables, HbA1C, hypertension and dyslipidemia. Further we showed risk of DPN is associated with increase in serum levels of sTNFRI (OR=11.2, p<10), sIL2Rα (8.69, p<10), sNTFRII (4.8, p<10) and MMP2 (4.5, p<10). We combined the serum concentration using ridge regression, into a composite score, which can stratify the DPN patients into low, medium and high-risk groups. Our results here show activation of inflammatory pathway in DPN patients, and could be a potential clinical tool to identify T1D patients for therapeutic intervention of anti-inflammatory therapies.
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http://dx.doi.org/10.3389/fimmu.2021.654233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044415PMC
March 2021

Niacin and Butyrate: Nutraceuticals Targeting Dysbiosis and Intestinal Permeability in Parkinson's Disease.

Nutrients 2020 Dec 23;13(1). Epub 2020 Dec 23.

Digestive Health Clinical Research Center, Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University, 1120, 15th St, Augusta, GA 30912, USA.

Dysbiosis is implicated by many studies in the pathogenesis of Parkinson's disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail.
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http://dx.doi.org/10.3390/nu13010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824468PMC
December 2020

Niacin Ameliorates Neuro-Inflammation in Parkinson's Disease via GPR109A.

Int J Mol Sci 2019 Sep 14;20(18). Epub 2019 Sep 14.

Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.

In this study, we used macrophage RAW264.7 cells to elucidate the molecular mechanism underlying the anti-inflammatory actions of niacin. Anti-inflammatory actions of niacin and a possible role of its receptor GPR109A have been studied previously. However, the precise molecular mechanism of niacin's action in reducing inflammation through GPR109A is unknown. Here we observed that niacin reduced the translocation of phosphorylated nuclear kappa B (p-NF-κB) induced by lipopolysaccharide (LPS) in the nucleus of RAW264.7 cells. The reduction in the nuclear translocation in turn decreased the expression of pro-inflammatory cytokines IL-1β, IL-6 in RAW264.7 cells. We observed a decrease in the nuclear translocation of p-NF-κB and the expression of inflammatory cytokines after knockdown of GPR109A in RAW264.7 cells. Our results suggest that these molecular actions of niacin are mediated via its receptor GPR109A (also known as HCAR2) by controlling the translocation of p-NF-κB to the nucleus. Overall, our findings suggest that niacin treatment may have potential in reducing inflammation by targeting GPR109A.
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http://dx.doi.org/10.3390/ijms20184559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770365PMC
September 2019

The dimensionality of fatigue in Parkinson's disease.

J Transl Med 2018 07 11;16(1):192. Epub 2018 Jul 11.

Department of Neurology, Augusta University, Augusta, Georgia, USA.

Background: Fatigue is a common problem among individuals with Parkinson's disease (PD). It may occur before the overt symptoms of bradykinesia, rigidity and tremor. Little is understood about how to measure fatigue in PD. Here we determined the dimensionality of the constructs of fatigue.

Methods: Four recommended scales, the Fatigue Severity Scale, Functional Assessment of Chronic Illness Therapy-Fatigue, Parkinson Fatigue Scale and Visual Analog Fatigue Scale (VAFS) were tested against quality of life measures including cognition, depression, sleep, life orientation, physical activity and PD symptoms in 22 PD subjects and 15 caregivers.

Results: Fatigue was associated with many quality of life variables, with the PDQ-39 summary index showing the strongest association. PD subjects agreed more strongly than caregivers that they experienced higher levels of fatigue. 27% of PD subjects rated fatigue as one of their top three most bothersome symptoms. The constructs of fatigue was captured within one dimension which explained 67% of the total variance, of which the VAFS showed the highest internal consistency. The highest likelihood ratio gave a cut-off score of < 5.5 on the VAFS. The change in scores required to produce a perceptible difference or is grossly observable ranged between 1.4 and 2.2 points respectively.

Conclusion: The potential utility of a single measure such as the VAFS in PD that is reliably correlated with quality of life is consistent with the pursuit to develop clinical tests and measurements that are accessible, easy to use and universally interpretable across health science disciplines.
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http://dx.doi.org/10.1186/s12967-018-1554-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040062PMC
July 2018

Niacin modulates macrophage polarization in Parkinson's disease.

J Neuroimmunol 2018 07 4;320:76-79. Epub 2018 May 4.

Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA; Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA. Electronic address:

Neuroinflammation remains a central piece in Parkinson's disease (PD) pathophysiology. However, mechanisms by which PD links to the neuroinflammation remain elusive. Here, for the first time, we report that lower dose of niacin in PD patients may affect macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) profile through the niacin receptor GPR109A. Skew in the peripheral macrophages were accompanied by improved quality of life assessments in patients. Low dose niacin supplementation may be beneficial in PD, boosting anti-inflammatory processes and suppressing inflammation. Varied niacin dosages for longer durations may further reveal the potential role of anti-inflammatory interventions in PD progression.
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http://dx.doi.org/10.1016/j.jneuroim.2018.05.002DOI Listing
July 2018

Constipation in Parkinson's Disease: a Nuisance or Nuanced Answer to the Pathophysiological Puzzle?

Curr Gastroenterol Rep 2018 Jan 19;20(1). Epub 2018 Jan 19.

Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University Medical Center, 1120 15th Street, AD-2226, Augusta, GA, 30912, USA.

Purpose Of Review: Chronic constipation is a common, nonmotor, and prodromal symptom in Parkinson's disease (PD). Its underlying neuropathology may provide pathophysiological insight into PD. Here, we critically review what is currently known about the neuroanatomical and brain-gut interactions, and the origin and progression of Lewy pathology (LP) at three levels-brain/brainstem, spinal cord, and enteric nervous system.

Recent Findings: Many recent studies have illustrated the challenges of examining LP in tissues obtained from colon biopsies of PD patients. Large-scale epidemiological studies have not confirmed the widely accepted Braakpostula. In this review, we propose an alternative origin and route of spread of LP in PD. We describe novel, noninvasive neurophysiological testing that could advance the understanding of LP and complex bidirectional brain-pelvic floor neural pathways in PD-a true disease model of a neurogastrointestinal disorder. This review may provide the impetus for future studies investigating gut and brain interaction and constipation in PD.
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http://dx.doi.org/10.1007/s11894-018-0609-xDOI Listing
January 2018

Low-dose niacin supplementation modulates GPR109A, niacin index and ameliorates Parkinson's disease symptoms without side effects.

Clin Case Rep 2015 Jul 11;3(7):635-7. Epub 2015 Jun 11.

Department of Neurology, Georgia Regents University 1120, 15th Street, Augusta, Georgia, 30912, USA.

A 65-year-old male, Parkinson's disease patient, was evaluated for GPR109A expression, niacin index, UPDRS scale, handwriting test, and quality of sleep with and without niacin treatment. The evaluation was repeated 3 months after niacin was stopped. Niacin modulated the abovementioned parameters and showed the overall improvement without side effects.
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http://dx.doi.org/10.1002/ccr3.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527813PMC
July 2015

A novel treatment target for Parkinson's disease.

J Neurol Sci 2014 Dec 23;347(1-2):34-8. Epub 2014 Oct 23.

Department of Physical Therapy, Georgia Regents University, Augusta, GA, USA. Electronic address:

We hypothesize that GPR109A message and expression are up-regulated in individuals with Parkinson's disease (PD). GPR109A is a high-affinity niacin receptor. Niacin is a precursor for NAD-NADH which is needed for dopamine production. Thus, niacin supplementation may serve three purposes: reduce inflammation through GPR109A-related mechanisms, increase dopamine synthesis in the striatum through NADPH supply and increase NAD/NADH ratio to boost mitochondrial functions. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina. However these roles are neither anticipated nor established in the CNS. For the first time here we propose the roles of GPR109A and its agonists including niacin in CNS pathology. Moreover we predict that the neuroprotective roles of either niacin or butyrates in CNS occur via GPR109A.
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http://dx.doi.org/10.1016/j.jns.2014.10.024DOI Listing
December 2014

Upregulation of GPR109A in Parkinson's disease.

PLoS One 2014 17;9(10):e109818. Epub 2014 Oct 17.

Department of Neurology, Georgia Regents University, Augusta, Georgia, United States of America.

Background: Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD.

Methods And Findings: GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-β, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep.

Conclusions: The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201464PMC
July 2015

Ganglioside GD3 is required for neurogenesis and long-term maintenance of neural stem cells in the postnatal mouse brain.

J Neurosci 2014 Oct;34(41):13790-800

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Department of Neurology, Medical College of Georgia, and Charlie Norwood VA Medical Center, Augusta, Georgia 30904

The maintenance of a neural stem cell (NSC) population in mammalian postnatal and adult life is crucial for continuous neurogenesis and neural repair. However, the molecular mechanism of how NSC populations are maintained remains unclear. Gangliosides are important cellular membrane components in the nervous system. We previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self-renewal capacity of NSCs in vitro. Here, we investigated its role in postnatal and adult neurogenesis in GD3-synthase knock-out (GD3S-KO) and wild-type mice. GD3S-KO mice with deficiency in GD3 and the downstream b-series gangliosides showed a progressive loss of NSCs both at the SVZ and the DG of the hippocampus. The decrease of NSC populations in the GD3S-KO mice resulted in impaired neurogenesis at the granular cell layer of the olfactory bulb and the DG in the adult. In addition, defects of the self-renewal capacity and radial glia-like stem cell outgrowth of postnatal GD3S-KO NSCs could be rescued by restoration of GD3 expression in these cells. Our study demonstrates that the b-series gangliosides, especially GD3, play a crucial role in the long-term maintenance NSC populations in postnatal mouse brain. Moreover, the impaired neurogenesis in the adult GD3S-KO mice led to depression-like behaviors. Thus, our results provide convincing evidence linking b-series gangliosides deficiency and neurogenesis defects to behavioral deficits, and support a crucial role of gangliosides in the long-term maintenance of NSCs in adult mice.
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http://dx.doi.org/10.1523/JNEUROSCI.2275-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188974PMC
October 2014

Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia.

J Steroid Biochem Mol Biol 2015 Feb 9;146:38-47. Epub 2014 May 9.

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address:

Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17β-estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia. This article is part of a Special Issue entitled "Sex steroids and brain disorders".
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http://dx.doi.org/10.1016/j.jsbmb.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419701PMC
February 2015

Axonal fasciculation and the role of polysialic acid-neural cell adhesion molecule in rat cortical neurons.

J Neurosci Res 2013 Nov 21;91(11):1408-18. Epub 2013 Aug 21.

Department of Physical Therapy, Georgia Regents University, Augusta, Georgia; Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, Georgia.

Axonal fasciculation is a mechanism deployed by growing axons to reach their targets during development of the nervous system. Published data have suggested the involvement of neuronal cell adhesion molecules (NCAM) in axonal fasciculation. We have characterized the formation of axonal fascicles in serum-free, primary cultures of cortical neurons from embryonic rat brains. Unlike the published data, axonal fascicles in our system have a unique morphology: they are waveform, are rarely thicker than 20 μm, and can reach up to several millimeters in length. We observed an age and time dependence in the formation of fascicles. They formed only in cultures from embryonic day 15-17 brain and only between 4 days in vitro (DIV) and 11 DIV. Electron microscopy showed that the fascicles consisted of mostly axonal processes. Immunocytochemical staining confirmed that the fascicles were positive for the 66-kDa neurofilament protein, NF66, but they contained few, if any, microtubule-associated protein-2-positive or glial fibrillary acidic protein-positive processes. Polysialic acids appeared to be critical in the formation of fascicles. Neuraminidase treatment prevented the formation of fascicles when added before 5 DIV. Addition of a specific inhibitor blocked the effect of neuraminidase. The cortical neurons in our model shared several important features with axon fasciculation in vivo and may provide a unique system for studying the molecular mechanisms involved in the formation of axonal tracts in the brain.
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http://dx.doi.org/10.1002/jnr.23268DOI Listing
November 2013

The pathological roles of ganglioside metabolism in Alzheimer's disease: effects of gangliosides on neurogenesis.

Int J Alzheimers Dis 2011 Jan 9;2011:193618. Epub 2011 Jan 9.

Institute of Molecular Medicine and Genetics and Institute of Neuroscience, Medical College of Georgia, 15th street, Augusta, GA 30912, USA.

Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed "GAβ", has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1-40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1-40 caused a significant reduction of cell number, suggesting that Aβ1-40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.
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http://dx.doi.org/10.4061/2011/193618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025365PMC
January 2011

Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain.

ASN Neuro 2010 Oct 4;2(4):e00044. Epub 2010 Oct 4.

Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, U.S.A.

The accumulation of Aβ (amyloid β-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Aβ. In the present study, we have examined ganglioside metabolism in the brain of a double-Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Aβ was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1α antigens (cholinergic neuron-specific gangliosides), such as GT1aα and GQ1bα, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Aβ.
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http://dx.doi.org/10.1042/AN20100021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948441PMC
October 2010

Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice.

J Neurosurg 2010 Dec 16;113(6):1195-201. Epub 2010 Apr 16.

Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia 30912, USA.

Object: Traumatic brain injury (TBI) induces significant neurological damage, including deficits in learning and memory, which contribute to a poor clinical prognosis. Treatment options to limit cognitive decline and promote neurological recovery are lacking, in part due to a poor understanding of the secondary or delayed processes that contribute to brain injury. In the present study, the authors characterized the temporal and spatial changes in the expression of postsynaptic density protein-95 (PSD-95), a key scaffolding protein implicated in excitatory synaptic signaling, after controlled cortical impacts in mice. Neurological injury, as assessed by the open-field activity test and the novel object recognition test, was compared with changes in PSD-95 expression.

Methods: Adult male CD-1 mice were subjected to controlled cortical impacts to simulate moderate TBI in humans. The spatial and temporal expression of PSD-95 was analyzed in the cerebral cortex and hippocampus at various time points following injury and sham operations. Neurological assessments were performed to compare changes in PSD-95 with cognitive deficits.

Results: A significant decrease in PSD-95 expression was observed in the ipsilateral hippocampus beginning on Day 7 postinjury. The loss of PSD-95 corresponded with a concomitant reduction in immunoreactivity for NeuN (neuronal nuclei), a neuron-specific marker. Aside from the contused cortex, a significant loss of PSD-95 immunoreactivity was not observed in the cerebral cortex. The delayed loss of hippocampal PSD-95 directly correlated with the onset of behavioral deficits, suggesting a possible causative role for PSD-95 in behavioral abnormalities following head trauma.

Conclusions: A delayed loss of hippocampal synapses was observed following head trauma in mice. These data may suggest a cellular mechanism to explain the delayed learning and memory deficits in humans after TBI and provide a potential framework for further testing to implicate PSD-95 as a clinically relevant therapeutic target.
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http://dx.doi.org/10.3171/2010.3.JNS091212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155981PMC
December 2010

Curcumin attenuates vascular inflammation and cerebral vasospasm after subarachnoid hemorrhage in mice.

Antioxid Redox Signal 2009 Jan;11(1):35-45

Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia 30912, USA.

Cerebral vasospasm is a major cause of death and disability after subarachnoid hemorrhage (SAH); however, clinical therapies to limit the development of cerebral vasospasm are lacking. Although the causative factors underlying the development of cerebral vasospasm are poorly understood, oxidative stress contributes to disease progression. In the present study, curcumin (150 or 300 mg/kg) protected against the development of cerebral vasospasm and limited secondary cerebral infarction after SAH in mice. The protective effect of curcumin was associated with a significant attenuation of inflammatory gene expression and lipid peroxidation within the cerebral cortex and the middle cerebral artery. Despite the ability of curcumin to limit the development of cerebral vasospasm and secondary infarction, behavioral outcome was not improved, indicating a dissociation between cerebral vasospasm and neurologic outcome. Together, these data indicate a novel role for curcumin as a possible adjunct therapy after SAH, both to prevent the development of cerebral vasospasm and to reduce oxidative brain injury after secondary infarction.
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http://dx.doi.org/10.1089/ars.2008.2056DOI Listing
January 2009

Hemin-induced necroptosis involves glutathione depletion in mouse astrocytes.

Free Radic Biol Med 2008 Oct 16;45(8):1103-14. Epub 2008 Jul 16.

Department of Neurosurgery, Medical College of Georgia, Augusta, GA 30912, USA.

Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1beta, TNF-alpha, iNOS). Inhibition of the NF-kappaB transcription factor reversed inflammatory gene expression and attenuated cell death after hemin treatment, suggesting a possible role for inflammatory mediators in astrocytic injury. Superoxide production paralleled the increase in iNOS expression, and inhibition of either iNOS (aminoguanidine or iminopiperdine) or superoxide (apocynin) significantly reduced cell death. Similarly, reduced formation of peroxynitrite, the damaging product of nitric oxide and superoxide, significantly reduced hemin injury. Hemin-induced peroxidative injury was associated with a rapid depletion of intracellular glutathione (GSH), culminating in lipid peroxidation and cell death, effects that were reduced by cotreatment with exogenous GSH, N-acetyl-L-cysteine, or the glutathione peroxidase mimetic ebselen. Together, these studies suggest a novel role for GSH depletion in necroptotic astrocyte injury after a hemorrhagic injury and indicate that therapeutic targeting of GSH may exert a beneficial effect after ICH.
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http://dx.doi.org/10.1016/j.freeradbiomed.2008.07.003DOI Listing
October 2008

Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase.

Endocrinology 2008 Jan 27;149(1):367-79. Epub 2007 Sep 27.

Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912, USA.

The purpose of this study was to enhance our understanding of the mechanisms of neuronal death after focal cerebral ischemia and the neuroprotective effects of tamoxifen (TMX). The phosphorylation state of 31 protein kinases/signaling proteins and superoxide anion (O(2)(-)) production in the contralateral and ipsilateral cortex was measured after permanent middle cerebral artery occlusion (pMCAO) in ovariectomized rats treated with placebo or TMX. The study revealed that pMCAO modulated the phosphorylation of a number of kinases/proteins in the penumbra at 2 h after pMCAO. Of significant interest, phospho-ERK1/2 (pERK1/2) was elevated significantly after pMCAO. TMX attenuated the elevation of pERK1/2, an effect correlated with reduced infarct size. In situ detection of O(2)(-) production showed a significant elevation at 1-2 h after pMCAO in the ischemic cortex with enhanced oxidative damage detected at 24 h. ERK activation may be downstream of free radicals, a suggestion supported by the findings that cells positive for O(2)(-) had high pERK activation and that a superoxide dismutase (SOD) mimetic, tempol, significantly attenuated pERK activation after MCAO. TMX treatment significantly reduced the MCAO-induced elevation of O(2)(-) production, oxidative damage, and proapoptotic caspase-3 activation. Additionally, pMCAO induced a significant reduction in the levels of manganese SOD (MnSOD), which scavenge O(2)(-), an effect largely prevented by TMX treatment, thus providing a potential mechanistic basis for the antioxidant effects of TMX. As a whole, these studies suggest that TMX neuroprotection may be achieved via an antioxidant mechanism that involves enhancement of primarily MnSOD levels, with a corresponding reduction of O(2)(-) production, and downstream kinase and caspase-3 activation.
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http://dx.doi.org/10.1210/en.2007-0899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194601PMC
January 2008

Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications.

Steroids 2007 May 21;72(5):381-405. Epub 2007 Feb 21.

Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, GA 30912, United States.

Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the Women's Health Initiative (WHI) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.
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http://dx.doi.org/10.1016/j.steroids.2007.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2048656PMC
May 2007

Induction of transforming growth factor-beta1 by basic fibroblast growth factor in rat C6 glioma cells and astrocytes is mediated by MEK/ERK signaling and AP-1 activation.

J Neurosci Res 2007 Apr;85(5):1033-45

Department of Neurosurgery, School of Medicine, Medical College of Georgia, Augusta, Georgia, USA.

Basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) play an important role in proliferation, differentiation, and survival of malignant gliomas and in normal glial cell biology. Because of these critical roles, potential interactions between these key growth factors were investigated. We previously demonstrated that bFGF potently stimulates TGF-beta1 release from rat glioma cells. The purpose of the present study was to elucidate the mechanism(s) of this regulatory effect, establish its functional importance, and examine whether it extends to nontransformed rat hypothalamic astrocytes (RHA). The results revealed that RHA express the high-affinity FGF(1-4) receptors, and similarly to glioma cells, bFGF stimulated TGF-beta1 release in an isoform-specific manner. A mediatory role for ERK signaling in bFGF-induced TGF-beta release was suggested by the fact that MEK1 inhibition prevented this effect. Additionally, bFGF enhanced MEK1/2 phosphorylation and ERK activation/nuclear translocation, which culminated in increased activity of AP-1-mediated gene transcription. bFGF markedly induced TGF-beta1 mRNA levels in an isoform-specific manner, an effect that was dependent on MEK/ERK/AP-1 signaling. Functionally, bFGF-induced proliferation of glioma cells was attenuated by MEK/ERK inhibition or immunoneutralization of TGF-beta1, suggesting that this pathway may have important implications for brain tumor progression.
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http://dx.doi.org/10.1002/jnr.21182DOI Listing
April 2007

Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB.

J Neurochem 2005 Oct;95(1):9-19

Department of Neurology and Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.

Stem cell factor (SCF) is a highly expressed cytokine in the central nervous system. In the present study, we demonstrate a neuroprotective role for SCF and its tyrosine kinase receptor, c-kit, against camptothecin-induced apoptosis and glutamate excitotoxicity in rat cortical neurons. This protection was blocked by pharmacological or molecular inhibition of either the MEK/ERK or PI3K/Akt signaling pathways. The importance of these pathways was further confirmed by the activation of both ERK, in a MEK-dependent manner, and Akt, via PI3K. Activation of Akt increased the binding of the p50 and p65 subunits of NFkappaB, which was also important for neuroprotection. Akt inhibition prevented NFkappaB binding, suggesting a role for Akt in SCF-induced NFkappaB. Pharmacological inhibition of NFkappaB or dominant negative IkappaB also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NFkappaB-dependent manner. Together, these findings demonstrate a neuroprotective role for SCF in cortical neurons, an effect that was mediated by Akt and ERK, as well as NFkappaB-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease.
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http://dx.doi.org/10.1111/j.1471-4159.2005.03319.xDOI Listing
October 2005

Cloning, expression, and localization of MNAR/PELP1 in rodent brain: colocalization in estrogen receptor-alpha- but not in gonadotropin-releasing hormone-positive neurons.

Endocrinology 2005 Dec 1;146(12):5215-27. Epub 2005 Sep 1.

Institute of Neuroscience, Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, 30912, USA.

MNAR/PELP1 is a recently identified scaffold protein in the human that modulates the nongenomic activity of estrogen receptors by facilitating linkage/cross talk with the Src/Erk activation cascade. We report herein the cloning of rat MNAR/PELP1 and provide new information concerning its distribution in the female rat brain and its degree of colocalization with estrogen receptor-alpha (ER-alpha) and GnRH. PCR-based cloning of MNAR/PELP1 from rat hypothalamus yielded a transcript of approximately 3.4 kb, which shows 86% homology to the published human MNAR/PELP1 sequence and retained all the key binding motifs (PXXP, LXXLL, and glutamic acid clusters) in its primary structure that are known to be critical for its interaction with Src and steroid receptors. RT-PCR revealed that the MNAR/PELP1 transcript is expressed in many regions of the brain, and immunohistochemistry studies showed intense MNAR/PELP1 immunoreactivity (MNAR/PELP1-ir) in areas such as the hypothalamus, cerebral cortex, hippocampus, amygdala, and cerebellum. MNAR/PELP1-ir principally localized in the nucleus, but some cytoplasmic and plasma membrane-associated staining was also observed. MNAR/PELP1-ir was also primarily neuronal, although some localization in glia cells was observed in select brain regions. Colocalization studies revealed that a majority of ER-alpha-positive cells in the brain colocalized MNAR/PELP1-ir. In contrast, MNAR/PELP1-ir rarely colocalized in GnRH neurons. In conclusion, the current study provides evidence that MNAR/PELP1 is expressed in key neural tissues of the rat brain that are known targets of steroid action, that its expression is primarily neuronal, and that MNAR/PELP1-ir is strongly colocalized in ER-alpha, but not GnRH neurons in the rodent brain.
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http://dx.doi.org/10.1210/en.2005-0276DOI Listing
December 2005

Differential expression of the peripheral benzodiazepine receptor and gremlin during adipogenesis.

Obes Res 2005 May;13(5):818-22

Medical College of Georgia, Institute of Molecular Medicine and Genetics, 1120 15th Street, Augusta, GA 30912, USA.

This study used the mRNA differential display technique to identify differentially expressed genes during the process of adipogenesis in the preadipocyte cell line, 3T3-L1. 3T3-L1 cells were treated with dexamethasone, isobutyl-1-methylxanthine, and insulin to induce differentiation into mature adipocytes. Cells were collected at three time-points during differentiation: Day 0 (d0), or nondifferentiated; Day 3 (d3), during differentiation; and Day 10 (d10), >90% of the cells had differentiated into mature adipocytes. Initial studies yielded 18 potentially differentially regulated cDNA candidates (8 down-regulated and 10 up-regulated). Reverse Northern and Northern blots confirmed differential expression of six of the candidates. Four of the candidates up-regulated on d3 and d10 were identified by sequence analysis to be lipoprotein lipase, a well-known marker of adipocyte differentiation. A fifth candidate that was expressed in d0, but not d3 or d10, was identified as DRM/gremlin, a bone morphogenetic protein antagonist. Finally, a sixth candidate that was increased at d3 and d10 was identified as the peripheral benzodiazepine receptor, which has been implicated in proliferation, differentiation, and cholesterol transport in cells. This study is the first to show that peripheral benzodiazepine receptor and DRM/gremlin are expressed in preadipocyte cell lines and that they are differentially regulated during adipogenesis.
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http://dx.doi.org/10.1038/oby.2005.93DOI Listing
May 2005

Atypical neuroleptics stimulate neurogenesis in adult rat brain.

J Neurosci Res 2002 Jul;69(1):72-9

Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.

Schizophrenia has been treated effectively with atypical neuroleptics without serious side effects. We have shown previously that long-term treatment with atypical neuroleptics is correlated with an improvement of cognition in adult rats. We report here that atypical neuroleptics stimulate a 2- to 3-fold increase in newly divided cells in the subventricular zone in the rat and that some of these new cells in the subventricular zone and hippocampus also express a neuronal marker. We used bromodeoxyuridine (BrdU) to identify newly divided cells and confirmed the observation with antibody to a cell-cycle-specific, endogenous proliferating cell nuclear antigen (PCNA). Identification of BrdU-positive cells in the anterior subventricular zone (SVZa) particularly in rats treated with the atypical neuroleptics but not in those in the haloperidol-treated and control rats, suggests increased rostral migratory stream (RMS) cell traffic to replenish neurons in the olfactory bulb. Expression of a neuronal marker, NeuN, in BrdU-positive cells in rats treated with atypical neuroleptics, also suggests that these compounds may modulate in vivo differentiation of neuronal progenitor cells even within a day of BrdU injection. Our results indicate that atypical neuroleptics have a mechanism of action other than the previously proposed mechanisms, which might explain their role in improved cognition in animal and in schizophrenic patients. If substantiated by future studies, our findings may lead to an expanded use of atypical neuroleptics in other neurodegenerative diseases to stimulate neuronal replacement and repair.
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http://dx.doi.org/10.1002/jnr.10281DOI Listing
July 2002