Ticagrelor as a dual RAS modulator and mitochondrial stabilizer: A multifaceted neurotherapeutic strategy in Huntington's disease.

The pathobiology of Huntington's disease (HD) is far from complete. Although limited, patients have been reported to exhibit altered platelet function, enhanced ENT1, and changes in renin-angiotensin system (RAS), all of which may impact cognitive function. Ticagrelor has demonstrated neuroprotective effects in stroke and parkinsonism models through mechanisms that extend beyond its therapeutic benefits as a P2Y12 receptor antagonist and ENT1 inhibitor. In this study, we investigated the potential efficiency Ticagrelor post-treatment on motor defects in a 3-nitropropionic acid (3-NP)-induced HD-like model. Symptomatic HD rats were daily treated for a week with Ticagrelor, the MAS receptor (MAS-R) antagonist A-779, or Ticagrelor + A-779. Ticagrelor amended body weight loss, motor function in open field and rotarod tests, and striatal histopathological alterations induced by 3-NP. On the striatal molecular level, Ticagrelor downregulated prorenin receptor mRNA expression but upregulated that of the MAS-R. Additionally, it decreased striatal contents of prorenin/renin and angiotensin II (Ang II), while increasing those of angiotensin-converting enzyme 2 and Ang-(1-7). Ticagrelor also hindered the phosphorylation/activation of the inositol trisphosphate receptor (IP3R), dynamin-related protein-1 (DRP-1), and PTEN-induced putative kinase 1 protein (PINK1) expressions. Additionally, it boosted the voltage-dependent anion channel-1 (VDAC-1) and Mitofusin-2 (Mnf-2) striatal contents. A-779 partially reverted Ticagrelor impact on all amendments except for prorenin receptor and p-IP3R. However, prorenin/renin correlated markedly with IP3R, DRP-1, and PINK1, but inversely with VDAC-1 and Mfn-2. In conclusion, Ticagrelor demonstrates promising neurotherapeutic effects in HD partially via the activation of MAS-R, inhibition of prorenin/renin/prorenin receptor, and improvement of mitochondrial homeostasis.