Related Experiment Video
Updated: Jan 14, 2026
Remotely Supervised Transcranial Direct Current Stimulation: An Update on Safety and Tolerability
Published on: October 7, 2017
Ticagrelor as a dual RAS modulator and mitochondrial stabilizer: A multifaceted neurotherapeutic strategy in
Ola E Mohamed1, Rabab H Sayed2, Dalaal M Abdallah3
1Postgraduate Program in Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12611, Egypt.
Insights
Ticagrelor improved motor function and striatal damage in an HD-like rat model. These neuroprotective effects involve MAS receptor activation and improved mitochondrial function, offering potential Huntington
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Huntington's disease (HD) pathobiology remains incompletely understood, with known alterations in platelet function, ENT1, and the renin-angiotensin system (RAS) potentially affecting cognition.
- Ticagrelor exhibits neuroprotective properties in models of stroke and parkinsonism, acting beyond its P2Y12 receptor antagonism and ENT1 inhibition.
Purpose of the Study:
- To investigate the efficacy of Ticagrelor post-treatment on motor deficits in a 3-nitropropionic acid (3-NP)-induced Huntington's disease-like rat model.
- To elucidate the molecular mechanisms underlying Ticagrelor's neuroprotective effects in this HD model, focusing on the renin-angiotensin system and mitochondrial homeostasis.
Main Methods:
- Symptomatic HD rats were treated daily for one week with Ticagrelor, the MAS receptor (MAS-R) antagonist A-779, or a combination of both.
- Evaluated motor function using open field and rotarod tests, and assessed striatal histopathological and molecular changes, including gene and protein expression related to RAS and mitochondrial dynamics.
Main Results:
- Ticagrelor treatment significantly improved body weight, motor function, and reduced striatal damage induced by 3-NP.
- Molecular analysis revealed Ticagrelor downregulated prorenin receptor and prorenin/renin, while upregulating MAS-R, ACE2, and Ang-(1-7). It also modulated mitochondrial proteins (IP3R, DRP-1, PINK1, VDAC-1, Mfn-2).
- The MAS-R antagonist A-779 partially reversed Ticagrelor's effects, suggesting a role for MAS-R activation.
Conclusions:
- Ticagrelor demonstrates significant neurotherapeutic potential in an HD-like model, ameliorating motor deficits and neurotoxicity.
- These benefits are partly mediated through MAS-R activation, modulation of the renin-angiotensin system, and restoration of mitochondrial homeostasis.
- The findings highlight Ticagrelor as a promising candidate for further investigation in Huntington's disease therapeutics.
Abstract:
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.
Related Concept Videos
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
01:24Parkinson's Disease: Treatment
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
01:25Antianginal Drugs: Calcium Channel Blockers and Ranolazine
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...