Abstract
Neurodegeneration and impaired neural development are a common feature of many neuropsychiatric disorders. Second-generation antipsychotics (SGAs) and certain atypical antidepressants display neuroprotective effects. Though these drugs interact with many molecular targets, a common shared attribute is high antagonist potency at 5-HT2A receptors. Pimavanserin is a selective 5-HT2A inverse agonist/antagonist that was recently FDA approved for treating hallucinations and delusions associated with Parkinson's disease. Unlike SGAs, pimavanserin lacks activity at other targets like dopamine, histamine, muscarinic, and adrenergic receptors. To investigate whether selective 5-HT2A inverse agonists have neuroprotective properties, pimavanserin and another selective 5-HT2A inverse agonist, M100907, were applied to primary cultures of dopaminergic neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Both pimavanserin and M100907 protected dopaminergic neurons against MPP+-induced cell death. The neuroprotective effects of pimavanserin required signaling through the extracellular signal-regulated kinase 1/2 pathway, restored mitochondrial function, and reduced oxidative stress. Further investigation showed that pimavanserin promotes the release of brain-derived neurotrophic factor and glial-derived neurotrophic factor (GDNF) and that the neuroprotective effects of pimavanserin were blocked by antibodies to GDNF but not by anti-tyrosine receptor kinase B receptor antibodies. Thus, pimavanserin induces release of neurotrophic factors and protects dopaminergic neurons against MPP+ toxicity in a GDNF-dependent manner.