Tripathi Ashutosh, Nasrallah Henry A, Pillai Anilkumar
Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States.
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States.
Front Neurosci. 2023 Aug 30;17:1237726. doi: 10.3389/fnins.2023.1237726. eCollection 2023.
Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play a key role in neuroplasticity and neurogenesis. The present study tested the hypothesis that treatment with Pimavanserin is associated with higher and sustained elevations of mBDNF.
Adult Sprague-Dawley male rats were treated with Pimavanserin, Fluoxetine or vehicle for 4 weeks (chronic) or 2 h (acute). BDNF levels were determined by enzyme-linked Immunosorbent assay (ELISA).
We found significant increases in plasma mBDNF levels in rats following chronic Pimavanserin treatment, but not in Fluoxetine-treated rats. No significant changes in mBDNF levels were found in the prefrontal cortex or hippocampus following Pimavanserin or Fluoxetine treatment.
These findings suggest that increase in mBDNF levels could be a contributing mechanism for the neuroprotective potential of Pimavanserin.
匹莫范色林是一种5-羟色胺5HT-2A受体反向激动剂，是美国食品药品监督管理局（FDA）批准的用于治疗帕金森病精神病（PDP）相关幻觉和妄想的一线药物，高达50%的帕金森病患者会出现这种情况。匹莫范色林治疗PDP的疗效背后的神经生物学机制尚不清楚。一些早期研究表明，用5HT-2A拮抗剂和其他作用于血清素能系统的药物（如选择性5-羟色胺再摄取抑制剂）治疗可提高啮齿动物脑源性神经营养因子（BDNF）水平。BDNF以前体proBDNF的形式合成，其在细胞内或细胞外进行切割以产生成熟的BDNF（mBDNF）蛋白。mBDNF被认为在神经可塑性和神经发生中起关键作用。本研究检验了以下假设：匹莫范色林治疗与mBDNF的更高且持续升高有关。
将成年Sprague-Dawley雄性大鼠用匹莫范色林、氟西汀或赋形剂治疗4周（慢性）或2小时（急性）。通过酶联免疫吸附测定（ELISA）测定BDNF水平。
我们发现，慢性匹莫范色林治疗后大鼠血浆mBDNF水平显著升高，但氟西汀治疗的大鼠未出现这种情况。匹莫范色林或氟西汀治疗后，前额叶皮质或海马体中的mBDNF水平未发现显著变化。
这些发现表明，mBDNF水平升高可能是匹莫范色林具有神经保护潜力的一个促成机制。
