A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide

The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disor ders. Based upon recent studies characterizing chemical inhibitors of p53 i n preclinical studies in the cancer therapy field, we synthesized the compo und pifithrin-alpha and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodege nerative disorders. Pifithrin-alpha protected neurons against apoptosis ind uced by DNA-damaging agents, amyloid beta -peptide and glutamate, Protectio n by pifithrin-alpha was correlated with decreased p53 DNA-binding activity , decreased expression of the p53 target gene Bax and suppression of mitoch ondrial dysfunction and caspase activation. Mice given pifithrin-alpha exhi bited increased resistance of cortical and striatal neurons to focal ischem ic injury and of hippocampal neurons to excitotoxic damage. These preclinic al studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 ma y reduce the extent of brain damage in related human neurodegenerative cond itions.