Neurotrophic factors are regarded as potential therapeutic tools in neurodegenerative disorders. Here, we analysed the protective effects of brain-derived neurotrophic factor, neurotrophin-3, glial cell line-derived neurotrophic factor and neurturin against the excitotoxic damage induced by kainate in striatal neurons in vitro and in vivo. Our results show that the decrease in the number of cultured striatal calbindinpositive neurons induced by kainate was prevented by treatment with any of these factors. To characterize their protective effects in vivo, cell lines overexpressing brainderived neurotrophic factor, neurotrophin-3, glial cell linederived neurotrophic factor or neurturin were grafted into the striatum. We found that the numbers of striatal projection neurons (calbindin-positive) and striatal interneurons (parvalbumin-or choline acetyltransferase-positive) were differentially decreased after kainate lesion. These neurotrophic factors prevented the loss of striatal projection neurons and interneurons with differing ef®ciency: brain-derived neurotrophic factor was the most ef®cient, whereas neurturin was the least. Our ®ndings show that brain-derived neurotrophic factor, neurotrophin-3, glial cell line-derived neurotrophic factor and neurturin have speci®c neuroprotective pro®les in striatal neurons and indicate that they are speci®c modulators of the survival of distinct subsets of striatal neurons in pathophysiological conditions.
Brain-derived neurotrophic factor (BDNF) prevents the loss of striatal neurons caused by excitotoxicity. We examined whether these neuroprotective effects are mediated by changes in the regulation of Bcl-2 family members. We first analyzed the involvement of the phosphatidylinositol 3-kinase/Akt pathway in this regulation, showing a reduction in phosphorylated Akt (p-Akt) levels after both quinolinate (QUIN, an NMDA receptor agonist) and kainate (KA, a non-NMDA receptor agonist) intrastriatal injection. Our results also show that Bcl-2, Bcl-x L and Bax protein levels and heterodimerization are selectively regulated by NMDA and non-NMDA receptor stimulation. Striatal cell death induced by QUIN is mediated by an increase in Bax and a decrease in Bcl-2 protein levels, leading to reduced levels of Bax:Bcl-2 heterodimers. In contrast, changes in Bax protein levels are not required for KA-induced apoptotic cell death, but decreased levels of both Bax:Bcl-2 and Bax:Bcl-x L heterodimer levels are necessary. Furthermore, QUIN and KA injection activated caspase-3. Intrastriatal grafting of a BDNF-secreting cell line counter-regulated p-AKT, Bcl-2, Bcl-x L and Bax protein levels, prevented changes in the heterodimerization between Bax and pro-survival proteins, and blocked caspase-3 activation induced by excitotoxicity. These results provide a possible mechanism to explain the anti-apoptotic effect of BDNF against to excitotoxicity in the striatum through the regulation of Bcl-2 family members, which is probably mediated by Akt activation. Keywords: apoptosis, basal ganglia, Bax knock-out, kainate, neurotrophic, quinolinate. Prolonged activation of glutamate receptors leads to neuronal death by excitotoxicity. In the central nervous system, this type of cell death has been associated with the development of chronic neurodegenerative disorders, such as Parkinson's disease and Huntington's chorea (Choi 1988;Alexi et al. 2000). Glutamate receptor overstimulation activates both necrotic and apoptotic pathways (Ferrer et al. 1995;Qin et al. 1996;Tenneti et al. 1998). In the past years, extensive research has been devoted to understanding the regulation of apoptosis as a potential route to the prevention of cell death in disease conditions. Indeed, apoptosis is mediated and regulated by intrinsic factors such as the Bcl-2 family (Cory and Adams 2002), and mechanisms such as mitochondrial release of cytochrome c (Li et al. 1997), and the activation of caspases (Yuan et al. 1993).The Bcl-2 family comprises at least 12 related proteins that can be divided into two groups according to functional criteria. Members of the first group, such as Bcl-2 and Bcl-x L , exhibit anti-apoptotic activity, whereas proteins of the second group exert pro-apoptotic effects, Bax being the prototypical member. These proteins can undergo various modifications in response to an apoptotic stimulus, including phosphorylation BCIP, 5-Bromo-4-chloro-3-indolyl-phosphate; BDNF, brain-derived neurotrophic factor; CNQX, 6-cyano-7-nitroquinoxaline-2,3-di...
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