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Brain‐derived neurotrophic factor prevents changes in Bcl‐2 family members and caspase‐3 activation induced by excitotoxicity in the striatum
Author(s) -
PérezNavarro Esther,
Gavaldà Núria,
Gratacòs Elena,
Alberch Jordi
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02904.x
Subject(s) - excitotoxicity , brain derived neurotrophic factor , neuroprotection , nmda receptor , neurotrophic factors , tropomyosin receptor kinase b , microbiology and biotechnology , neurotrophin , protein kinase b , striatum , biology , chemistry , receptor , neuroscience , signal transduction , biochemistry , dopamine
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.