Pimavanserin Promotes Trophic Factor Release and Protects Cultured Primary Dopaminergic Neurons Exposed to MPP+ in a GDNF-Dependent Manner
| Autor: | Dorothée Buttigieg, Rémy Steinschneider, Elodie Gras Lavigne, Ethan S. Burstein |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
1-Methyl-4-phenylpyridinium
Physiology Cognitive Neuroscience Pimavanserin Pharmacology Biochemistry Neuroprotection 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines Neurotrophic factors Dopamine Glial cell line-derived neurotrophic factor medicine Inverse agonist Urea Glial Cell Line-Derived Neurotrophic Factor 030304 developmental biology Brain-derived neurotrophic factor 0303 health sciences biology Dopaminergic Neurons Dopaminergic Cell Biology General Medicine Neuroprotective Agents chemistry biology.protein 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | ACS chemical neuroscience. 12(12) |
| ISSN: | 1948-7193 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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