BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP+-induced toxicity in cultured hippocampal and mesencephalic slices.

Neurotoxicity is involved in various neurodegenerative diseases including Parkinson's disease (PD), which affects mesencephalic dopaminergic neurons of the substantia nigra (SN). Positive alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators (PARMs, a.k.a. Ampakines, such as CX614) increase brain-derived neurotrophic factor (BDNF) protein levels in vivo and in cultured hippocampal slices. BDNF is a survival factor for various neuronal cell types including mesencephalic dopaminergic neurons. Using cultured mesencephalic and hippocampal slices, we investigated whether preincubation with CX614 could provide neuroprotection against MPP(+) toxicity and whether such neuroprotection was mediated by BDNF. Various treatment protocols were tested to demonstrate CX614-induced neuroprotection against MPP(+). Pretreatment with CX614 significantly reduced MPP(+)-induced toxicity and increased BDNF levels in both hippocampal and mesencephalic cultured slices; CX614 pretreatment for 6 h in hippocampal slices and 24 h in mesencephalic slices was sufficient to produce significant neuroprotection as assessed with lactate dehydrogenase release in slice medium and propidium iodide uptake in slices. Both a BDNF scavenger and an inhibitor of the BDNF receptor TrkB, abrogated CX614-mediated reduction of MPP(+)-induced toxicity. Inhibition of Ca(2+)-activated proteases, calpains, was also protective against MPP(+)-induced toxicity. However, co-application of calpain inhibitor with CX614 abolished CX614-mediated protection, suggesting a dual action of calpains in this model. We conclude that CX614 is neuroprotective against MPP(+)-induced toxicity, an effect mediated by increased BDNF expression and activation of BDNF-dependent signaling pathways. Our results provide support for using PARMs as a new therapy for neurodegenerative disorders, including PD.