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1.
Mol Ther ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34563674

RESUMO

Spontaneous recovery after a stroke accounts for a significant part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used magnetic resonance imaging, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

2.
J Neurochem ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34569615

RESUMO

Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive due to low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R overexpressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate activated protein kinase (AMPK) via use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-ß and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-ß. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.

3.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
4.
Curr Aging Sci ; 14(1): 1-2, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34028346
5.
Sci Rep ; 11(1): 9711, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958667

RESUMO

An evaluation of the APPswe/PS1dE9 transgenic AD mouse, presenting with the toxic Aß1-42 deposition found in human AD, allowed us to characterize time-dependent changes in inflammatory and cholinergic markers present in AD. Astrogliosis was observed in cortex and hippocampus, with cellular loss occurring in the same areas in which Aß plaques were present. In this setting, we found early significantly elevated levels of IL-1ß and TNFα gene expression; with the hippocampus showing the highest IL-1ß expression. To investigate the cholinergic anti-inflammatory pathway, the expression of nicotinic receptors (nAChRs) and cholinesterase enzymes also was evaluated. The anti-inflammatory nAChRα7, α4, and ß2 were particularly increased at 6 months of age in the hippocampus, potentially as a strategy to counteract Aß deposition and the ensuing inflammatory state. A time-dependent subunit switch to the α3ß4 type occurred. Whether α3, ß4 subunits have a pro-inflammatory or an inhibitory effect on ACh stimulation remains speculative. Aß1-42 deposition, neuronal loss and increased astrocytes were detected, and a time-dependent change in components of the cholinergic anti-inflammatory pathway were observed. A greater understanding of time-dependent Aß/nAChRs interactions may aid in defining new therapeutic strategies and novel molecular targets.

6.
Cells ; 10(5)2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922642

RESUMO

Circulating neuronal extracellular vesicles (NEVs) of Alzheimer's disease (AD) patients show high Tau and ß-amyloid (Aß) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. To validate EV proteins as AD biomarkers, we immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels. NEVs from 3xTg-AD mice had higher total Tau (p = 0.03) and p181-Tau (p = 0.0004) compared to WT mice. There were moderately strong correlations between biomarkers in NEVs and cerebral cortex and hippocampus (total Tau: cortex, r = 0.4, p = 0.009; p181-Tau: cortex, r = 0.7, p < 0.0001; hippocampus, r = 0.6, p < 0.0001). NEVs from 5xFAD compared to other mice had higher Aß42 (p < 0.005). NEV Aß42 had moderately strong correlations with Aß42 in cortex (r = 0.6, p = 0.001) and hippocampus (r = 0.7, p < 0.0001). AEV C1q was elevated in 3xTg-AD compared to WT mice (p = 0.005); AEV C1q had moderate-strong correlations with C1q in cortex (r = 0.9, p < 0.0001) and hippocampus (r = 0.7, p < 0.0001). Biomarkers in circulating NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as a "liquid biopsy" for neurological disorders.

7.
J Cereb Blood Flow Metab ; 41(7): 1579-1591, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33203296

RESUMO

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 KATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1M146V) 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-ß (Aß) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor Nω-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 PS1M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aß oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1M146V mutation.

8.
Molecules ; 25(23)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33276504

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidores da Angiogênese/farmacologia , Aorta/efeitos dos fármacos , Simulação de Acoplamento Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Inibidores da Angiogênese/química , Animais , Simulação por Computador , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
9.
Elife ; 92020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32804078

RESUMO

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.


Assuntos
Biomarcadores/sangue , Concussão Encefálica , Quimiocinas , Citocinas , Animais , Lesões Encefálicas/patologia , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Córtex Cerebral/patologia , Quimiocina CXCL16/análise , Quimiocina CXCL16/genética , Quimiocina CXCL16/metabolismo , Quimiocinas/análise , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/análise , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Ontologia Genética , Redes Reguladoras de Genes , Camundongos , Transcriptoma , Fator B de Crescimento do Endotélio Vascular/análise , Fator B de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo
10.
Front Neurosci ; 14: 785, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848559

RESUMO

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.

11.
Elife ; 92020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32589144

RESUMO

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.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Encefalite/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
12.
Expert Opin Investig Drugs ; 29(6): 595-602, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32412796

RESUMO

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.


Assuntos
Antiparkinsonianos/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Doença de Parkinson/tratamento farmacológico , Animais , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Front Aging Neurosci ; 12: 31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32116655

RESUMO

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 Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo 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 Drosophila LRRK2WD40 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. LRRK2WD40 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. LRRK2WD40 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 LRRK2WD40 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.

14.
Transl Psychiatry ; 10(1): 81, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123156

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
iScience ; 23(2): 100866, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32058974

RESUMO

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 Ca++i and ER stress.

16.
Transl Psychiatry ; 10(1): 47, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066688

RESUMO

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-ß peptide (Aß) generated from its precursor protein (APP) by ß-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 Aß 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.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases , Humanos , Camundongos , Ratos , Rivastigmina
17.
FASEB J ; 34(2): 3359-3366, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31916313

RESUMO

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.


Assuntos
Astrócitos/metabolismo , Lesões Encefálicas Traumáticas/sangue , Proteínas do Sistema Complemento/metabolismo , Exossomos/metabolismo , Biomarcadores/sangue , Lesões Encefálicas Traumáticas/patologia , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Adulto Jovem
18.
Exp Neurol ; 324: 113135, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31778663

RESUMO

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-1ß 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.


Assuntos
Autofagia/efeitos dos fármacos , Benzotiazóis/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Encefalite/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antioxidantes/metabolismo , Comportamento Animal , Contusão Encefálica/tratamento farmacológico , Contusão Encefálica/patologia , Contusão Encefálica/psicologia , Lesões Encefálicas Traumáticas/psicologia , Citocinas/metabolismo , Encefalite/patologia , Heme Oxigenase (Desciclizante)/biossíntese , Masculino , Ratos , Ratos Sprague-Dawley , Tolueno/uso terapêutico
19.
CNS Neurosci Ther ; 26(6): 636-649, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31828969

RESUMO

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.

20.
Exp Neurol ; 324: 113113, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31730763

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Linhagem Celular , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ácido Glutâmico/toxicidade , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/administração & dosagem , Nootrópicos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos
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