Scholarlink

<p>Neuroinflammation is considered to be a most vibrant molecular event in Alzheimer’s disease (AD) which is mainly triggered by accumulation of misfolded amyloid-β (Aβ) in neuronal cells. The Aβ mediated neuroinflammatory cascades further initiates the downstream neurodegenerative events through acceleration of microglial immune responses and oxidative stress persuaded mitochondrial dysfunction. The purinergic receptor, or P2X7 receptor, is measured as a pattern recognition element that is instantly activated by Aβ induced ATP release. This activation of P2X7 receptor further facilitates the NEK7-mediated NLRP3 activation. NLRP3 acts as a vital molecular mediator in the maturation of IL-1β and exacerbating the inflammatory responses in neurons. Along with inflammatory responses, Aβ also initiates Ca<sup>2+</sup> influx-related mitochondrial toxicity, including Cyt-c release &amp; ROS production. This dynamic neurotoxic pathway ultimately leads to neuronal cell death and exhibits severe neurodegeneration. Here, we hypothesized that Pioglitazone (PPAR-γ agonist) in combination with Nimodipine (L-type calcium channel blocker) may synergistically inhibit several steps in the P2X7 receptor-facilitated NLRP3 pathway and may possibly reduce the IL-1β production. Additionally, Nimodipine and Pioglitazone, were also reported to reduce the Aβ dependent Cyt-c release and ROS mediated mitochondrial biogenesis. This novel combination has the potential to attenuate the Aβ dependent detrimental cascades of AD along with their established protective mechanisms. Molecular docking studies further suggested potential interaction of Nimodipine and pioglitazone with P2X7 and NEK7 respectively suggesting the potential for these compounds, in addition to the known pharmacological activity discussed above, to influence inflammatory signal transduction. Therefore, Nimodipine and Pioglitazone can be a plausible combination to target the multifaceted AD pathogenesis and may represent a potential combination of AD therapy; however, the proposed mechanisms remain predictive and require systematic biochemical, cell-based and in-vivo validations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Navigating the maze of Alzheimer’s: nimodipine and pioglitazone combination in the spotlight through inhibition of P2X7 dependent NLRP3 inflammasome activation

  • 期刊论文

  • 发表日期：

    2026年4月15日

查看全文
  • Antony Justin,
  • Chennu Manisha,
  • Sayani Banerjee,
  • Gopika Venu,
  • A. Vignesh Pandi

摘要

Neuroinflammation is considered to be a most vibrant molecular event in Alzheimer’s disease (AD) which is mainly triggered by accumulation of misfolded amyloid-β (Aβ) in neuronal cells. The Aβ mediated neuroinflammatory cascades further initiates the downstream neurodegenerative events through acceleration of microglial immune responses and oxidative stress persuaded mitochondrial dysfunction. The purinergic receptor, or P2X7 receptor, is measured as a pattern recognition element that is instantly activated by Aβ induced ATP release. This activation of P2X7 receptor further facilitates the NEK7-mediated NLRP3 activation. NLRP3 acts as a vital molecular mediator in the maturation of IL-1β and exacerbating the inflammatory responses in neurons. Along with inflammatory responses, Aβ also initiates Ca2+ influx-related mitochondrial toxicity, including Cyt-c release & ROS production. This dynamic neurotoxic pathway ultimately leads to neuronal cell death and exhibits severe neurodegeneration. Here, we hypothesized that Pioglitazone (PPAR-γ agonist) in combination with Nimodipine (L-type calcium channel blocker) may synergistically inhibit several steps in the P2X7 receptor-facilitated NLRP3 pathway and may possibly reduce the IL-1β production. Additionally, Nimodipine and Pioglitazone, were also reported to reduce the Aβ dependent Cyt-c release and ROS mediated mitochondrial biogenesis. This novel combination has the potential to attenuate the Aβ dependent detrimental cascades of AD along with their established protective mechanisms. Molecular docking studies further suggested potential interaction of Nimodipine and pioglitazone with P2X7 and NEK7 respectively suggesting the potential for these compounds, in addition to the known pharmacological activity discussed above, to influence inflammatory signal transduction. Therefore, Nimodipine and Pioglitazone can be a plausible combination to target the multifaceted AD pathogenesis and may represent a potential combination of AD therapy; however, the proposed mechanisms remain predictive and require systematic biochemical, cell-based and in-vivo validations.