Activation of alpha-7 nicotinic acetylcholine receptor by tropisetron mitigates 3-nitropropionic acid-induced Huntington's disease in rats: Role of PI3K/Akt and JAK2/NF-κB signaling pathways.

Autor: Rabie MA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt. Electronic address: Mostafa.mohammed@pharma.cu.edu.eg., Ghoneim AT; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt., Fahmy MI; Department of Pharmacology and Toxicology, College of Pharmaceutical sciences and drug manufacturing, Misr University for Science and Technology (MUST), 12585, Giza, Egypt., El-Yamany MF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt., Sayed RH; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt; School of Pharmacy, Newgiza University, Giza, Egypt.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Apr 25; Vol. 393, pp. 110957. Date of Electronic Publication: 2024 Mar 19.
DOI: 10.1016/j.cbi.2024.110957
Abstrakt: Huntington's disease (HD) is an inheritable autosomal-dominant disorder that targets mainly the striatum. 3-Nitropropionic acid (3-NP) induces obvious deleterious behavioral, neurochemical, and histological effects similar to the symptoms of HD. Our study aimed to examine the neuroprotective activity of tropisetron, an alpha-7 neuronal nicotinic acetylcholine receptor (α-7nAChR) agonist, against neurotoxic events associated with 3-NP-induced HD in rats. Forty-eight rats were randomly allocated into four groups. Group I received normal saline, while Groups II, III and IV received 3-NP for 2 weeks. In addition, Group III and IV were treated with tropisetron 1 h after 3-NP administration. Meanwhile, Group IV received methyllycaconitine (MLA), an α-7nAChR antagonist, 30 min before tropisetron administration. Treatment with tropisetron improved motor deficits as confirmed by the behavioral tests and restored normal histopathological features of the striatum. Moreover, tropisetron showed an anti-oxidant activity via increasing the activities of SDH and HO-1 as well as Nrf2 expression along with reducing MDA level. Tropisetron also markedly upregulated the protein expression of p-PI3K and p-Akt which in turn hampered JAK2/NF-κB inflammatory cascade. In addition, tropisetron showed an anti-apoptotic activity through boosting the expression of Bcl-2 and reducing Bax expression and caspase-3 level. Interestingly, all the aforementioned effects of tropisetron were blocked by pre-administration of MLA, which confirms that such neuroprotective effects are mediated via activating of α-7nAChR. In conclusion, tropisetron showed a neuroprotective activity against 3-NP-induced HD via activating PI3K/Akt signaling and suppressing JAK2/NF-κB inflammatory axis. Thus, repositioning of tropisetron could represent a promising therapeutic strategy in management of HD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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