Antidepressant-like effects of chronic guanosine in the olfactory bulbectomy mouse model

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression

Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system

Ureases are microbial virulence factors either because of the enzymatic release of ammonia or due to many other non-enzymatic effects. Here we studied two neurotoxic urease isoforms, Canatoxin (CNTX) and Jack Bean Urease (JBU), produced by the plant Canavalia ensiformis, whose mechanisms of action remain elusive. The neurotoxins provoke convulsions in rodents (LD50 ∼2 mg/kg) and stimulate exocytosis in cell models, affecting intracellular calcium levels. Here, electrophysiological and brain imaging techniques were applied to elucidate their mode of action. While systemic administration of the toxins causes tonic-clonic seizures in rodents, JBU injected into rat hippocampus induced spike-wave discharges similar to absence-like seizures. JBU reduced the amplitude of compound action potential from mouse sciatic nerve in a tetrodotoxin-insensitive manner. Hippocampal slices from CNTX-injected animals or slices treated in vitro with JBU failed to induce long term potentiation upon tetanic stimulation. Rat cortical synaptosomes treated with JBU released L-glutamate. JBU increased the intracellular calcium levels and spontaneous firing rate in rat hippocampus neurons. MicroPET scans of CNTX-injected rats revealed increased Fluoro-deoxyglucose uptake in epileptogenesis-related areas like hippocampus and thalamus. Curiously, CNTX did not affect voltage-gated sodium, calcium or potassium channels currents, neither did it interfere on cholinergic receptors, suggesting an indirect mode of action that could be related to the ureases' membrane-disturbing properties. Understanding the neurotoxic mode of action of C. ensiformis ureases could help to unveil the so far underappreciated relevance of these toxins in diseases caused by urease-producing microorganisms, in which the human central nervous system is affected

Crises convulsivas associadas à hipóxia neonatal e o potencial uso terapêutico do neuropeptídeo NAP = Hypoxia-associated neonatal seizures and potential therapeutic use of neuropeptide NAP

Objetivo: apresentar dados de revisão sobre os aspectos clínicos e fisiopatológicos das crises convulsivas neonatais associadas à hipóxia, as bases celulares e moleculares envolvidas neste processo e as evidências experimentais e clínicas da possível utilização terapêutica do neuropeptídeo NAP nesta condição. Fonte de dados: para a captação dos artigos utilizou-se a base de dados PubMed, inserindo os termos NAP, neonatal seizures e perinatal hypoxia. O critério de seleção de artigos foi a especificidade em relação ao tema estudado, preferencialmente a partir do ano de 1990. Além disso, foram utilizados também artigos clássicos de anos anteriores que se aplicavam ao propósito desta revisão. Síntese de dados: o risco de apresentar crises convulsivas está aumentado no período neonatal. Existem dificuldades no diagnóstico das crises, eficácia limitada do tratamento e potenciais efeitos adversos, dos anticonvulsivantes utilizados correntemente, no desenvolvimento cerebral dos recém-nascidos. Frente à urgência de novas estratégias para o tratamento das complicações resultantes de crises convulsivas neonatais associadas à hipóxia, o peptí- deo NAP torna-se um forte candidato, considerando sua ação neuroprotetora em diversos modelos animais e em ensaios clínicos. Com estudos adicionais, o peptídeo NAP poderá ser empregado como novo agente terapêutico para a prevenção da hipóxia cerebral e das seqüelas das crises convulsivas em recémnascidos. Conclusões: apesar dos indícios positivos da aplicação do peptídeo NAP em modelos animais de neuropatologias e de seu sucesso preliminar em ensaios clínicos, são necessárias pesquisas adicionais a fim de entender particularidades desse composto, tais como mecanismo de ação e viabilidade clínica para o tratamento das crises convulsivas neonatai