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1.
Neuropharmacology ; 138: 210-218, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29842858

RESUMO

The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task. Pharmacological enhancement of 2-AG tone facilitated memory consolidation through activation of CB2 receptor signaling. Moreover, we found that increased 2-AG signaling prevented the activation of the mammalian target of rapamycin (mTOR) signaling pathway in the hippocampus through a CB2-dependent mechanism. Our results identify a fundamental role for 2-AG and CB2 receptors in the modulation of memory consolidation for aversive experiences.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Hidrólise/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Benzodioxóis/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Consolidação da Memória/fisiologia , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Piperidinas/farmacologia , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
J Alzheimers Dis ; 38(2): 281-93, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23948942

RESUMO

One of the hallmarks of Alzheimer's disease (AD), the most common age-related neurodegenerative pathology, is the abnormal extracellular deposition of neurotoxic amyloid-ß (Aß) peptides that accumulate in senile plaques. Aß aggregates are toxic to neurons and are thought to contribute to neuronal loss. Evidence indicates that inflammation is involved in the pathophysiology of AD, and activation of glial cells by a variety of factors, including Aß, appears to be a central event. Among molecules produced during inflammation associated with neuronal death, CCL2, also known as monocyte chemotactic protein-1 (MCP-1), seems to be particularly important. Indeed, CCL2 levels are higher in the cerebrospinal fluid of patients with AD than in controls. In the present study, we demonstrated the protective effect of bindarit (which inhibits CCL2 synthesis) against both Aß25-35 and Aß1-42-induced toxicity in primary mixed neural cultures. Bindarit (30-500 µM) reversed cell death induced by Aß in a dose-dependent manner and reduced the transcription and release of CCL2 by astrocytes after Aß treatment, as revealed by qRT-PCR, ELISA, and immunofluorescence staining. Astroglial activation and CCL2 release was induced by ATP released by damaged neurons through interaction with P2X7 receptors present on astrocyte surface. CCL2, interacting with its cognate receptor CCR2, present on neuron surface, strongly contributes to the toxic activity of Aß. Bindarit was able to disconnect this neuro-glial interaction. Our results demonstrate the ability of bindarit to inhibit Aß-induced neuronal death and suggest the potential role of CCL2 inhibitors in the treatment of neuroinflammatory/neurodegenerative diseases.


Assuntos
Quimiocina CCL2/metabolismo , Indazóis/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Propionatos/farmacologia , Trifosfato de Adenosina/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Quimiocina CCL2/genética , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neurônios/ultraestrutura , Fragmentos de Peptídeos/toxicidade , Gravidez , Ratos , Ratos Wistar
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