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1.
Circulation ; 135(16): 1532-1546, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28202489

RESUMO

BACKGROUND: Pulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension. METHODS: Plasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension. Nampt+/- mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells. RESULTS: Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension. Nampt+/- mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia-induced pulmonary hypertension in rats. CONCLUSIONS: Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Nicotinamida Fosforribosiltransferase/uso terapêutico , Artéria Pulmonar/fisiopatologia , Remodelação Vascular/efeitos dos fármacos , Animais , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotinamida Fosforribosiltransferase/administração & dosagem , Nicotinamida Fosforribosiltransferase/farmacologia , Ratos , Ratos Sprague-Dawley , Transfecção
2.
Cell Res ; 32(6): 570-584, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35459935

RESUMO

The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.


Assuntos
NAD , Nicotinamida Fosforribosiltransferase , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/uso terapêutico
3.
BMC Res Notes ; 15(1): 189, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35606882

RESUMO

OBJECTIVE: The present study aimed to investigate the effects of nano-curcumin supplementation on adipokines levels and clinical signs in obese and overweight patients with migraine. RESULTS: Forty-four patients with episodic migraine participated in this clinical trial and were divided into two groups nano-curcumin (80 mg/day) and the control group over 2-month period. At the baseline and the end of the research, the serum levels of MCP-1, Resistin, and Visfatin were measured using the ELISA method. In addition, the headache attack frequencies, severity, and duration of pain were recorded. The results of the present study showed that nano-curcumin can significantly reduce MCP-1 serum levels in the nano-curcumin supplemented group (P = 0.015, size effect = 13.4%). In the case of resistin and visfatin, nano-curcumin supplementation exerted no statistically significant changes in serum levels (P > 0.05). Nano-curcumin also significantly reduced the attack frequencies, severity, and duration of headaches (P < 0.05). These findings indicate that targeting curcumin can be a promising approach to migraine management. However, further comprehensive human trials are needed to confirm these findings. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20160626028637N2 on the date 2020-07-10.


Assuntos
Curcumina , Transtornos de Enxaqueca , Adipocinas , Curcumina/uso terapêutico , Suplementos Nutricionais , Método Duplo-Cego , Humanos , Irã (Geográfico) , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Resistina
4.
Arch Immunol Ther Exp (Warsz) ; 69(1): 11, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856572

RESUMO

Visfatin is a multifunctional protein involved in inflammatory immune stress. The aim of current study was to explore the role of visfatin in lipopolysaccharide (LPS)-induced intestinal mucosal inflammation and to confirm its cellular effect in inflammatory immune response through silencing of Toll-like receptors (TLRs). We divided Kunming mice into three groups: Saline group, LPS group, and LPS + visfatin group and performed hematoxylin and eosin staining, immunohistochemistry, quantitative polymerase chain reaction, Western blot, enzyme linked immunosorbent assay and RNA-seq analysis. Pretreatment of visfatin improves LPS-stimulated reduction of tight junction protein 1 (ZO-1) and secretory immunoglobulin A, inhibits overexpression of Claudin-1 and vascular endothelial growth factor, and reduces intestinal mucosal damage and inflammation. RNA-seq analysis of cellular transcriptomes indicated that visfatin is involved in down-regulation of mRNA level of TLR4 as well as attenuation of protein levels of TLR8 and nucleotide-binding oligomerization domain-containing protein 2, revealing that visfatin could reduce intestinal mucosal inflammation through TLR signaling pathway in mice ileum. In RAW264.7 cells, the genes silencing of Toll/IL-1R family, such as TLR4, TLR2, and IL-1R1, was accompanied by decreased expressions of inflammatory factors (TNF-α, IL-1ß, IL-6 and MCP-1) along with lower cellular visfatin levels. Hence, visfatin maintains the intestinal mucosal barrier structure and attenuates the intestinal mucosal inflammation through the TLR signaling pathway. Likewise, the Toll/IL-1R family regulates the release of visfatin, which can participate in the inflammatory reaction through the regulation of inflammatory factors.


Assuntos
Mediadores da Inflamação/antagonistas & inibidores , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Nicotinamida Fosforribosiltransferase/uso terapêutico , Células RAW 264.7 , RNA-Seq , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo
5.
Curr Opin Pharmacol ; 9(2): 202-7, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19081303

RESUMO

The adipocytokine, visfatin, exerts a diverse variety of effects that include the ability to mimic the glucose-lowering effects of insulin. In addition to its anti-hyperglycaemic action, recent evidence suggests that visfatin may be responsible for a number of different cardiovascular effects, depending on the cell type and the duration of therapy, one of which includes the ability to protect the myocardium from the detrimental effects of acute ischaemia-reperfusion injury. As such visfatin may not only provide a potential new target for acute cardioprotection but it may also act as an anti-diabetic agent with a unique mechanism of action, thereby offering a potentially novel drug target for the diabetic patient that experiences an episode of acute myocardial ischaemia-reperfusion injury.


Assuntos
Cardiotônicos/uso terapêutico , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/uso terapêutico , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Cardiotônicos/farmacologia , Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle
6.
Stroke Vasc Neurol ; 4(2): 83-89, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31338216

RESUMO

Stroke is the second and the leading most common cause of death in the world and China, respectively, but with few effective therapies. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD) salvage synthesis in mammals, thereby influencing NAD-dependent enzymes and constituting a strong endogenous defence system against various stresses. Accumulating in-vitro and in-vivo studies have demonstrated the neuroprotective effect of NAMPT in stroke. Here, we review the direct evidence of NAMPT as a promising target against stroke from five potential therapeutic strategies, including NAMPT overexpression, recombinant NAMPT, NAMPT activators, NAMPT enzymatic product nicotinamide mononucleotide (NMN), and NMN precursors nicotinamide riboside and nicotinamide, and describe the relevant mechanisms and limitations, providing a promising choice for developing novel and effective therapeutic interventions against ischaemic and haemorrhagic stroke.


Assuntos
Encéfalo/efeitos dos fármacos , Citocinas/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Acidente Vascular Cerebral Hemorrágico/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Nicotinamida Fosforribosiltransferase/uso terapêutico , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Citocinas/agonistas , Citocinas/metabolismo , Ativação Enzimática , Ativadores de Enzimas/efeitos adversos , Acidente Vascular Cerebral Hemorrágico/enzimologia , Acidente Vascular Cerebral Hemorrágico/fisiopatologia , Humanos , AVC Isquêmico/enzimologia , AVC Isquêmico/fisiopatologia , Terapia de Alvo Molecular , Fármacos Neuroprotetores/efeitos adversos , Nicotinamida Fosforribosiltransferase/metabolismo , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais
7.
PLoS One ; 14(2): e0212523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794635

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD)+ biosynthesis. Through its NAD+-biosynthetic activity, NAMPT influences the activity of NAD+-dependent enzymes, such as sirtuins. NAMPT is able to modulate processes involved in the pathogenesis of non-alcohol induced fatty liver disease (NAFLD), but the roles NAMPT plays in development of alcoholic liver disease (ALD) still remain unknown. Here, we show that ethanol treatment suppresses the expression of Nampt in hepatocytes. Consistently, chronic ethanol administration also reduces Nampt expression in the mouse liver. We next demonstrate that hepatocytes infected with Ad-NAMPT adenovirus exhibit significantly elevated intracellular NAD+ levels and decreased ethanol-induced triglyceride (TG) accumulation. Similarly, adenovirus-mediated overexpression of NAMPT in mice ameliorates ethanol induced hepatic steatosis. Moreover, we demonstrate that SIRT1 is required to mediate the effects of NAMPT on reduction of hepatic TG accumulation and serum ALT, AST levels in ethanol-fed mice. Our results provide important insights in targeting NAMPT for treating alcoholic fatty liver disease.


Assuntos
Citocinas/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/terapia , Nicotinamida Fosforribosiltransferase/metabolismo , Adenoviridae/genética , Animais , Células Cultivadas , Citocinas/genética , Citocinas/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Etanol/toxicidade , Fígado Gorduroso Alcoólico/genética , Técnicas de Silenciamento de Genes , Terapia Genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/uso terapêutico , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuínas/deficiência , Sirtuínas/genética , Sirtuínas/metabolismo , Triglicerídeos/metabolismo , Regulação para Cima
8.
Clin Endocrinol (Oxf) ; 68(2): 317-20, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18031315

RESUMO

BACKGROUND AND AIM: Low-dose pioglitazone (Pio), flutamide (Flu), metformin (Met) plus an oestro-progestagen is a novel polytherapy lowering total and visceral adiposity, and reducing carotid intima media thickness (IMT) in hyperinsulinaemic women with androgen excess, without changing their body mass index (BMI). In a search for mediators of PioFluMet's actions, we measured serum levels of visfatin and high molecular weight (HMW) adiponectin. DESIGN AND PATIENTS: In a double-blind study, we enrolled 38 young women with hyperinsulinaemic androgen excess [mean BMI: 23.7 kg/m(2)], all of whom started on Flu (62.5 mg/day), Met (850 mg/day) and a transdermal oestro-progestagen, each for 21/28 days over 1 year. Patients were randomly assigned to receive, in addition, placebo (n = 19) or Pio (7.5 mg/day; n = 19) on the same 21/28 days. MEASUREMENTS: Serum concentrations of visfatin and HMW adiponectin, visceral fat by magnetic resonance imaging, carotid IMT by ultrasound, all carried out during study start and after 1 year. RESULTS: PioFluMet raised visfatin by a mean 84% and HMW adiponectin by 157% (P < 0.001), and reduced visceral fat and IMT by a mean 22% and 31% (both P < 0.001). Low-dose Pio accounted for about half of the PioFluMet effects on IMT, visfatin and HMW adiponectin. CONCLUSION: In hyperinsulinaemic women with androgen excess, low-dose polytherapy with PioFluMet evoked striking rises in both circulating visfatin and HMW adiponectin, while lowering IMT and reducing visceral adiposity within 1 year.


Assuntos
Adiponectina/metabolismo , Flutamida/uso terapêutico , Hiperandrogenismo/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Metformina/uso terapêutico , Nicotinamida Fosforribosiltransferase/uso terapêutico , Tiazolidinedionas/uso terapêutico , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Hiperandrogenismo/sangue , Nicotinamida Fosforribosiltransferase/sangue , Pioglitazona , Adulto Jovem
9.
CNS Neurosci Ther ; 22(6): 431-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27018006

RESUMO

Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration.


Assuntos
Doenças do Sistema Nervoso/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Humanos , NAD/farmacologia , NAD/uso terapêutico , Doenças do Sistema Nervoso/enzimologia , Neurogênese/fisiologia , Mononucleotídeo de Nicotinamida/farmacologia , Mononucleotídeo de Nicotinamida/uso terapêutico
10.
J Mol Neurosci ; 56(1): 237-43, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25603815

RESUMO

Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin (Nampt/PBEF/visfatin) is an adipocytokine. By synthesizing nicotinamide adenine dinucleotide (NAD(+)), Nampt/PBEF/visfatin functions to maintain an energy supply that has critical roles in cell survival. Cerebral ischemia leads to energy depletion and eventually neuronal death by apoptosis in specific brain regions specially the hippocampus. However, the role of Nampt/PBEF/visfatin in brain and cerebral ischemia remains to be investigated. This study investigated the role of administration Nampt/PBEF/visfatin in hippocampal CA3 area using a transient global cerebral ischemia model. Both common carotid arteries were occluded for 20 min followed by reperfusion. Saline as a vehicle and Nampt/PBEF/visfatin at a dose of 100 ng were injected intracerebroventricularly (ICV) at the time of cerebral reperfusion. To investigate the underlying mechanisms of Nampt/PBEF/visfatin neuroprotection, levels of expression of apoptosis-related proteins (caspase-3 activation, Bax protein levels, and Bcl-2 protein levels) 96 h after ischemia were determined by immunohistochemical staining. The number of active caspase-3-positive neurons in CA3 was significantly increased in the ischemia group, compared with the sham group (P < 0.001), and treatment with Nampt/PBEF/visfatin significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P < 0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in the ischemia group, compared with the sham group (P < 0.01). However, treatment with Nampt/PBEF/visfatin significantly attenuated the ischemia/reperfusion-induced increase in Bax/Bcl-2 ratio, compared with the ischemia group (P < 0.05). This study has indicated that Nampt/PBEF/visfatin entails neuroprotective effects against ischemia injury when used at the time of cerebral reperfusion. These neuroprotective mechanisms of Nampt/PBEF/visfatin occur through decrease the expression ofproapoptotic proteins (cleaved caspase-3 and Bax) and, on the other hand, increase the expression ofantiapoptotic proteins (Bcl-2). Thus, our findings indicate that Nampt/PBEF/visfatin is a new therapeutic target for cerebral ischemia.


Assuntos
Caspase 3/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Nicotinamida Fosforribosiltransferase/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Região CA1 Hipocampal/irrigação sanguínea , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Nicotinamida Fosforribosiltransferase/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo
11.
CNS Neurosci Ther ; 20(6): 539-47, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24750959

RESUMO

AIM: Visfatin, a novel adipokine, is predominantly produced by visceral adipose tissue and exists in intracellular and extracellular compartments. The intracellular form of visfatin is proved to be nicotinamide phosphoribosyltransferase (NAMPT) and exhibits neuroprotection through maintaining intracellular NAD(+) pool. However, whether extracellular form of visfatin has NAMPT activity and the effect of extracellular visfatin in cerebral ischemia are unknown. METHODS AND RESULTS: Plasma concentrations of visfatin, NAD(+) , and ATP were increased in mice upon cerebral ischemia. Cultured glia, but not neuron, was able to secrete visfatin. Oxygen-glucose deprivation (OGD) stress increased the secretion of visfatin from glia. Extracellular recombinant mouse wild-type visfatin, but not mouse H247A-mutant enzymatic-dead visfatin, had NAMPT enzymatic function in vitro. Treatment of wild-type visfatin, but not H247A-mutant enzymatic-dead visfatin, significantly attenuated detrimental effect of OGD on the cell viability and apoptosis in both cultured mouse neuron and glia. Treatment of neutralizing antibody, abolished the protective effect of extracellular visfatin on cell viability, but failed to block the antiapoptotic effect of extracellular visfatin. At last, we observed that plasma visfatin concentrations decreased in 6-month-old but not 3-month-old SHR-SP compared with that in age-matched Wistar-Kyoto rats. Inhibition of NAMPT enzymatic function of visfatin (by FK866) accelerated the occurrence of stroke in SHR-SP. CONCLUSIONS: Extracellular visfatin has NAMPT enzymatic activity and maybe be neuroprotective just as intracellular visfatin in cerebral ischemic injury.


Assuntos
Isquemia Encefálica/enzimologia , Líquido Extracelular/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Nicotinamida Fosforribosiltransferase/uso terapêutico , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Líquido Extracelular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/enzimologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/sangue , Nicotinamida Fosforribosiltransferase/sangue , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/imunologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética
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