Minocycline attenuates microglial activation but fails to mitigate degeneration in inferior olive and pontine nuclei after focal cerebellar lesion.
ABSTRACT Degenerative changes in areas remote from the primary lesion site have been linked to the clinical outcome of focal brain damage, and inflammatory mechanisms have been considered to play a key role in the pathogenesis of these remote cell death phenomena. Minocycline is a tetracycline derivative, therapeutically effective in various experimental models of central nervous system (CNS) injuries that include inflammatory and apoptotic mechanisms, although recent findings have yielded mixed results. In this study, we investigated the effectiveness of minocycline treatment in reducing remote cell death. Glial activation and neuronal loss in precerebellar stations following cerebellar lesion were investigated using immunohistochemistry and Western blot techniques. Our results show that minocycline was effective in reducing microglial activations in axotomized precerebellar nuclei, but failed to mitigate either astrocytic response or neuronal loss. This finding supports the role of minocycline in modulating inflammatory response after CNS lesion and suggests its ineffectiveness in influencing degenerative phenomena in areas remote from the primary lesion site.
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ABSTRACT: Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development.DNA research: an international journal for rapid publication of reports on genes and genomes 03/2010; 8(1):41-61. · 1.73 Impact Factor
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ABSTRACT: Hemicerebellectomy results in remote delayed degeneration of precerebellar neurons. We have reported that such a lesion induces type 2 cannabinoid receptor (CB(2)) expression in precerebellar neurons and that stimulation of CB(2), but not CB(1), has neuroprotective effects. In this study, we found that in the same model, the CB(2) agonist JWH-015 enhances neuronal nitric oxide synthase (nNOS) expression in axotomized neurons and that CB(2)-mediated neuroprotection is abrogated by pharmacological inhibition of nNOS. JWH-015 prevented the axotomy-induced upregulation of inducible NOS (iNOS) in astrocytes but had no effect on endothelial NOS (eNOS). In addition, we observed that JWH-015 significantly reduces hemicerebellectomy-induced neuroinflammatory responses and oxidative/nitrative stress. With regard to the signaling pathways of CB(2)/nNOS-mediated neuroprotection, we noted nNOS-dependent modulation of the expression of anti-oxidative (Hsp70) and anti-apoptotic (Bcl-2) proteins. These findings shed light on the interactions between the endocannabinoid and nitrergic systems after focal brain injury, implicating distinct functions of nNOS activation and iNOS inhibition in CB(2) signaling, which protect neurons from axotomy-induced cell death.Journal of Molecular Medicine 12/2011; 90(4):371-87. · 4.67 Impact Factor