Publications by authors named "Nigel H Greig"

258 Publications

Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment.

Front Psychiatry 2021 5;12:536257. Epub 2021 Mar 5.

Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.

Cytokines are one of the most important components of the immune system. They orchestrate the brain's response to infectious and other exogenous insults and are crucial mediators of the cross-talk between the nervous and immune systems. Epidemiological studies have demonstrated that severe infections and autoimmune disorders, in addition to genetic predisposition, are risk factors for schizophrenia. Furthermore, maternal infection during pregnancy appears to increase the risk of schizophrenia, and proinflammatory cytokines may be negatively involved in the neurodevelopmental process. A cytokine imbalance has been described in the blood and cerebrospinal fluid of schizophrenia patients, particularly in the T helper type 1 [Th1] and type 2 [Th2] cytokines, albeit the results of such studies appear to be contradictory. Chronic stress, likewise, appears to contribute to a lasting proinflammatory state and likely also promotes the disorder. The aim of this mini-review is to investigate the roles of different cytokines in the pathophysiology of schizophrenia and define how cytokines may represent key molecular targets to regulate for the prevention and treatment of schizophrenia. How current antipsychotic drugs impact cytokine networks is also evaluated. In this context, we propose to change the focus of schizophrenia from a traditionally defined brain disorder, to one that is substantially impacted by the periphery and immune system.
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http://dx.doi.org/10.3389/fpsyt.2021.536257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973221PMC
March 2021

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs.

Molecules 2020 Dec 2;25(23). Epub 2020 Dec 2.

Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.
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http://dx.doi.org/10.3390/molecules25235683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730988PMC
December 2020

Age-related impairment of cerebral blood flow response to K channel opener in Alzheimer's disease mice with presenilin-1 mutation.

J Cereb Blood Flow Metab 2020 Nov 17:271678X20964233. Epub 2020 Nov 17.

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer's disease (AD). In this study, regional CBF (rCBF) responses to the K channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%-40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1 mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1 contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1 mutation.
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http://dx.doi.org/10.1177/0271678X20964233DOI Listing
November 2020

PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson's Disease.

Front Neurosci 2020 11;14:785. Epub 2020 Aug 11.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

Background: We previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide (exendin-4) plasma and target levels in 6-hydroxydopamine (6-OHDA)-pretreated animals. Additionally, pre- or post-treatment with PT320 mitigated the early stage of 6-OHDA-induced dopaminergic neurodegeneration. The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson's disease.

Methods: Adult male Sprague-Dawley rats were unilaterally lesioned in the right medial forebrain bundle by 6-OHDA. L-DOPA and benserazide were given daily for 22 days, starting from 4 weeks after lesioning. PT320 was co-administered weekly for 3 weeks. AIM was evaluated on days 1, 16, and 22 after initiating L-DOPA/benserazide + PT320 treatment. Brain tissues were subsequently collected for HPLC measurements of dopamine (DA) and metabolite concentrations.

Results: L-DOPA/benserazide increased AIMs of limbs and axial as well as the sum of all dyskinesia scores (ALO) over 3 weeks. PT320 significantly reduced the AIM scores of limbs, orolingual, and ALO. Although PT320 did not alter DA levels in the lesioned striatum, PT320 significantly attenuated 6-OHDA-enhanced DA turnover.

Conclusion: PT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rat model of PD and warrants clinical evaluation to mitigate Parkinson's disease in humans.
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http://dx.doi.org/10.3389/fnins.2020.00785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431885PMC
August 2020

Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury.

Elife 2020 08 17;9. Epub 2020 Aug 17.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, United States.

Traumatic brain injury (TBI) is a serious global health problem, many individuals live with TBI-related neurological dysfunction. A lack of biomarkers of TBI has impeded medication development. To identify new potential biomarkers, we time-dependently evaluated mouse brain tissue and neuronally derived plasma extracellular vesicle proteins in a mild model of TBI with parallels to concussive head injury. Mice (CD-1, 30-40 g) received a sham procedure or 30 g weight-drop and were euthanized 8, 24, 48, 72, 96 hr, 7, 14 and 30 days later. We quantified ipsilateral cortical proteins, many of which differed from sham by 8 hours post-mTBI, particularly GAS-1 and VEGF-B were increased while CXCL16 reduced, 23 proteins changed in 4 or more of the time points. Gene ontology pathways mapped from altered proteins over time related to pathological and physiological processes. Validation of proteins identified in this study may provide utility as treatment response biomarkers.
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http://dx.doi.org/10.7554/eLife.55827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473773PMC
August 2020

3,6'-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation.

Elife 2020 06 26;9. Epub 2020 Jun 26.

Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States.

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.
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http://dx.doi.org/10.7554/eLife.54726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375814PMC
June 2020

Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease.

Expert Opin Investig Drugs 2020 Jun 15;29(6):595-602. Epub 2020 May 15.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health , Baltimore, MD, USA.

Introduction: Accumulating evidence supports the evaluation of glucagon-like peptide-1 (GLP-1) receptor (R) agonists for the treatment of the underlying pathology causing Parkinson's Disease (PD). Not only are these effects evident in models of PD and other neurodegenerative disorders but recently in a randomized, double-blind, placebo-controlled clinical trial, a GLP-1R agonist has provided improved cognition motor functions in humans with moderate PD.

Areas Covered: In this mini-review, we describe the development of GLP-1R agonists and their potential therapeutic value in treating PD. Many GLP-1R agonists are FDA approved for the treatment of metabolic disorders, and hence can be rapidly repositioned for PD. Furthermore, we present preclinical data offering insights into the use of monomeric dual- and tri-agonist incretin-based mimetics for neurodegenerative disorders. These drugs combine active regions of GLP-1 with those of glucose-dependent insulinotropic peptide (GIP) and/or glucagon (Gcg).

Expert Opinion: GLP-1Ragonists offer a complementary and enhanced therapeutic value to other drugs used to treat PD. Moreover, the use of the dual- or tri-agonist GLP-1-based mimetics may provide combinatory effects that are even more powerful than GLP-1R agonism alone. We advocate for further investigations into the repurposing of GLP-1R agonists and the development of classes of multi-agonists for PD treatment.
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http://dx.doi.org/10.1080/13543784.2020.1764534DOI Listing
June 2020

Correction: Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease.

Transl Psychiatry 2020 Mar 2;10(1):81. Epub 2020 Mar 2.

Department of Psychiatry, Laboratory of Molecular Neurogenetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41398-020-0757-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052148PMC
March 2020

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the LRRK2 Genetic Model of Parkinson's Disease.

Front Aging Neurosci 2020 13;12:31. Epub 2020 Feb 13.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

The search for new disease-modifying drugs for Parkinson's disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2), is a simple model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the LRRK2 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM's actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans.
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http://dx.doi.org/10.3389/fnagi.2020.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031158PMC
February 2020

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease.

Transl Psychiatry 2020 02 3;10(1):47. Epub 2020 Feb 3.

Department of Psychiatry, Laboratory of Molecular Neurogenetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases- Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.
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http://dx.doi.org/10.1038/s41398-020-0709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026402PMC
February 2020

Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain.

iScience 2020 Feb 28;23(2):100866. Epub 2020 Jan 28.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Acetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic α7 cholinergic receptor activation. The use of AChE inhibitors in patients is limited by systemic cholinergic side effects. Posiphen, a stereoisomer of the AChE inhibitor Phenserine, lacks AChE inhibitor activity. The purpose of this study is to determine the protective effect of Posiphen in cellular and animal models of stroke. Both Posiphen and Phenserine reduced glutamate-mediated neuronal loss in co-cultures of primary cortical cells and microglia. Phenserine-, but not Posiphen-, mediated neuroprotection was diminished by the nicotinic α7 receptor antagonist methyllycaconitine. Posiphen antagonized NMDA-mediated Ca influx, thapsigargin-mediated neuronal loss and ER stress in cultured cells. Early post-treatment with Posiphen reduced ER stress signals, IBA1 immunoreactivity, TUNEL and infarction in the ischemic cortex, as well as neurological deficits in stroke rats. These findings indicate that Posiphen is neuroprotective against stroke through regulating Cai and ER stress.
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http://dx.doi.org/10.1016/j.isci.2020.100866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013187PMC
February 2020

Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury.

Front Cell Dev Biol 2019 10;7:356. Epub 2020 Jan 10.

Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders.
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http://dx.doi.org/10.3389/fcell.2019.00356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965031PMC
January 2020

Traumatic brain injury increases plasma astrocyte-derived exosome levels of neurotoxic complement proteins.

FASEB J 2020 02 8;34(2):3359-3366. Epub 2020 Jan 8.

Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.

Possible involvement of complement (C) systems in the pathogenesis of traumatic brain injury (TBI) was investigated by quantifying Cproteins in plasma astrocyte-derived exosomes (ADEs) of subjects with sports-related TBI (sTBI) and TBI in military veterans (mtTBI) without cognitive impairment. All sTBI subjects (n = 24) had mild injuries, whereas eight of the mtTBI subjects had moderate, and 17 had mild injuries. Plasma levels of ADEs were decreased after acute sTBI and returned to normal within months. Cprotein levels in ADEs were from 12- to 35-fold higher than the corresponding levels in neuron-derived exosomes. CD81 exosome marker-normalized ADE levels of classical pathway C4b, alternative pathway factor D and Bb, lectin pathway mannose-binding lectin (MBL), and shared neurotoxic effectors C3b and C5b-9 terminal C complex were significantly higher and those of C regulatory proteins CR1 and CD59 were lower in the first week of acute sTBI (n = 12) than in controls (n = 12). Most C abnormalities were no longer detected in chronic sTBI at 3-12 months after acute sTBI, except for elevated levels of factor D, Bb, and MBL. In contrast, significant elevations of ADE levels of C4b, factor D, Bb, MBL, C3b and C5b-9 terminal C complex, and depressions of CR1 and CD59 relative to those of controls were observed after 1-4 years in early chronic mtTBI (n = 10) and persisted for decades except for normalization of Bb, MBL, and CD59 in late chronic mtTBI (n = 15). Complement inhibitors may be useful therapeutically in acute TBI and post-concussion syndrome.
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http://dx.doi.org/10.1096/fj.201902842RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459190PMC
February 2020

Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments.

Front Cell Dev Biol 2019 4;7:313. Epub 2019 Dec 4.

Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.

Neuroinflammation is initiated when glial cells, mainly microglia, are activated by threats to the neural environment, such as pathogen infiltration or neuronal injury. Although neuroinflammation serves to combat these threats and reinstate brain homeostasis, chronic inflammation can result in excessive cytokine production and cell death if the cause of inflammation remains. Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that target the 3'-untranslated region (3'-UTR) of TNF-α mRNA, inhibiting TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs such as 3,6'-dithiothalidomide and adamantyl thalidomide derivatives, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression. In this review, we evaluate the role of neuroinflammation in neurodegenerative diseases, focusing specifically on the role of TNF-α in neuroinflammation, as well as appraise current research on the potential of IMiDs as treatments for neurological disorders.
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http://dx.doi.org/10.3389/fcell.2019.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904283PMC
December 2019

(-)-Phenserine tartrate (PhenT) as a treatment for traumatic brain injury.

CNS Neurosci Ther 2020 06 11;26(6):636-649. Epub 2019 Dec 11.

Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Aim: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely.

Discussion: We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman.

Conclusion: In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.
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http://dx.doi.org/10.1111/cns.13274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248544PMC
June 2020

The p53 inactivators pifithrin-μ and pifithrin-α mitigate TBI-induced neuronal damage through regulation of oxidative stress, neuroinflammation, autophagy and mitophagy.

Exp Neurol 2020 02 26;324:113135. Epub 2019 Nov 26.

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei 110, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei 110, Taiwan. Electronic address:

Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-μ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-μ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-μ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-μ. Double immunofluorescence staining similarly demonstrated that PFT-μ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-μ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-μ lowered TBI-induced pro-inflammatory cytokines (IL-1β and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-μ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-μ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-μ, in particular, holds promise as a TBI treatment strategy.
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http://dx.doi.org/10.1016/j.expneurol.2019.113135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792017PMC
February 2020

Geriatric pharmacotherapy: Appraising new drugs for neurologic disorders in older patients.

Handb Clin Neurol 2019 ;167:3-18

Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States. Electronic address:

New drug development for neurologic disorders has one of the highest attrition rates of all clinical drug developments. This is problematic when, with innovative technology available in so many aspects of life, modern societies expect to have effective treatments for neurodegenerative disorders and mental health conditions that provide something beyond simple symptomatic relief-the expectation is treatment that impacts and mitigates fundamental mechanisms that drive these disorders. The disease burden of neurologic disorders remains extremely high, whereas the proportion of patients receiving effective therapy is relatively low, demonstrating a sizeable unmet medical need. Whether for novel breakthrough therapies or for drugs considered successful, deciding on the basis of clinical trial data whether a particular treatment will be effective for a specific patient is always a leap of faith. However, expertise at reading trial results combined with knowledge of the patient and of his or her disease, together with an understanding of the effect of age on drug pharmacokinetics and pharmacodynamics, the effect of age on the patient's condition, and the effect of age on the patient's life and outlook will ensure the landing is safe. The focus of this article is to provide such knowledge and thereby optimize this expertise.
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http://dx.doi.org/10.1016/B978-0-12-804766-8.00001-7DOI Listing
April 2020

Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon.

Sci Rep 2019 11 20;9(1):17208. Epub 2019 Nov 20.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

The time-dependent (30 min - day 84) plasma profile of PT320, a sustained-release (SR)-Exenatide formulation under clinical development for treatment of neurodegenerative disorders, was evaluated in nonhuman primates after a single subcutaneous dose and was compared to Bydureon. Exenatide release from PT320 exhibited a triphasic pharmacokinetic profile. An initial peak occurred at 3 hr post-administration, a secondary peak at 5 days, and achievement of Exenatide steady-state plasma levels from day 10-28. Systemic exposure increased across PT320 doses, and Exenatide levels were maintained above the therapeutic threshold prior to achieving a steady-state. In contrast, Exenatide release from Bydureon exhibited a biphasic profile, with an initial plasma peak at 3 hr, followed by a rapid decline to a sub-therapeutic concentration, and a gradual elevation to provide a steady-state from day 35-49. Exenatide total exposure, evaluated from the area under the time-dependent Exenatide concentration curve, was similar for equivalent doses of PT320 and Bydureon. The former, however, reached and maintained steady-state plasma Exenatide levels more rapidly, without dipping to a sub-therapeutic concentration. Both SR-Exenatide formulations proved well-tolerated and, following a well-regulated initial release burst, generated steady-state plasma levels of Exenatide, but with PT320 producing continuous therapeutic Exenatide levels and more rapidly reaching a steady-state.
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http://dx.doi.org/10.1038/s41598-019-53356-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868133PMC
November 2019

Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury.

Exp Neurol 2020 02 12;324:113113. Epub 2019 Nov 12.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address:

A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy.
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http://dx.doi.org/10.1016/j.expneurol.2019.113113DOI Listing
February 2020

A Pilot Study of Exenatide Actions in Alzheimer's Disease.

Curr Alzheimer Res 2019 ;16(8):741-752

Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States.

Background: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD).

Objective: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD.

Method: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone.

Results: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.

Conclusion: The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.
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http://dx.doi.org/10.2174/1567205016666190913155950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476877PMC
October 2020

Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury.

ACS Pharmacol Transl Sci 2019 Apr 11;2(2):66-91. Epub 2019 Feb 11.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.
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http://dx.doi.org/10.1021/acsptsci.9b00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687335PMC
April 2019

Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease.

Mov Disord 2019 12 23;34(12):1818-1830. Epub 2019 Jul 23.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

Background: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model.

Methods: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control.

Results: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels.

Conclusions: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27799DOI Listing
December 2019

(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice.

Neurobiol Dis 2019 10 8;130:104528. Epub 2019 Jul 8.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address:

Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.
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http://dx.doi.org/10.1016/j.nbd.2019.104528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716152PMC
October 2019

(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice.

Cell Transplant 2019 Sep-Oct;28(9-10):1183-1196. Epub 2019 Jun 10.

The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei.

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.
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http://dx.doi.org/10.1177/0963689719854693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767878PMC
August 2020

Pomalidomide Reduces Ischemic Brain Injury in Rodents.

Cell Transplant 2019 04 16;28(4):439-450. Epub 2019 May 16.

1 The PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei.

Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM's neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.
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http://dx.doi.org/10.1177/0963689719850078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628558PMC
April 2019

Pifithrin-Alpha Reduces Methamphetamine Neurotoxicity in Cultured Dopaminergic Neurons.

Neurotox Res 2019 Aug 8;36(2):347-356. Epub 2019 May 8.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

Methamphetamine (Meth) is a widely abused stimulant. High-dose Meth induces degeneration of dopaminergic neurons through p53-mediated apoptosis. A recent study indicated that treatment with the p53 inhibitor, pifithrin-alpha (PFT-α), antagonized Meth-mediated behavioral deficits in mice. The mechanisms underpinning the protective action of PFT-α against Meth have not been identified, and hence, their investigation is the focus of this study. Primary dopaminergic neuronal cultures were prepared from rat embryonic ventral mesencephalic tissue. High-dose Meth challenge reduced tyrosine hydroxylase immunoreactivity and increased terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling. PFT-α significantly antagonized these responses. PFT-α also reduced Meth-activated translocation of p53 to the nucleus, an initial step before transcription. Previous studies have indicated that p53 can also activate cell death through transcription-independent pathways. We found that PFT-α attenuated endoplasmic reticulum (ER) stressor thapsigargin (Tg)-mediated loss of dopaminergic neurons. ER stress was further monitored through the release of Gaussia luciferase (GLuc) from SH-SY5Y cells overexpressing GLuc-based Secreted ER Calcium-Modulated Protein (GLuc-SERCaMP). Meth or Tg significantly increased GLuc release in to the media, with PFT-α significantly reducing GLuc release. Additionally, PFT-α significantly attenuated Meth-induced CHOP expression. In conclusion, our data indicate that PFT-α is neuroprotective against Meth-mediated neurodegeneration via transcription-dependent nuclear and -independent cytosolic ER stress pathways.
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http://dx.doi.org/10.1007/s12640-019-00050-wDOI Listing
August 2019

Is insulin resistance the cause of fibromyalgia? A preliminary report.

PLoS One 2019 6;14(5):e0216079. Epub 2019 May 6.

Pain and Headache Center, Eagle River, Alaska, United States of America.

Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216079PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502334PMC
May 2019