Huntington's disease (HD) is a devastating neurodegenerative disease primarily caused by autosomal inherited mutation, resulting in various psychological, motor, and cognitive deficits [1]. This genetic disorder is mediated by expanded CAG trinucleotide repeat in huntingtin (Htt) gene [2], resulting in mutation of huntingtin protein that mediates the neurological and motor symptoms of HD [1]. Although numerous cerebral regions show signs of neurodegeneration in HD, the striatum is recognized as the most prominently affected area [3,4]. 3-Nitropropionic acid (3-NP) is a natural mycotoxin that irreversibly inhibits the activity of the mitochondrial enzyme succinate dehydrogenase (SDH) resulting in impairment of mitochondrial respiratory chain with a subsequent depletion of cellular energy metabolism in the striatum. Consequently, a prominent reduction in ATP production occurs leading to a remarkable striatal damage that mimics the morphological and neurochemical alterations of HD, alongside with various gait abnormalities [5]. Therefore, systemic administration of 3-NP is considered as a well-established animal model for HD induction.

According to epidemiological research, smoking is considered as one of the most intriguing factors influencing the incidence of HD. Previous studies have shown that smokers have a lower risk of neurodegenerative disorders than non-smokers. This finding was thought to be related to the activation of nicotinic receptors by nicotine, a nonselective agonist of alpha 7 nicotinic receptor (α-7nAChR) [6]. Besides, several research teams have investigated the potential effects of α-7nAChR agonists in different neurodegenerative disorders experimental models [7]. α-7nAChRs are ligand-gated calcium ion channels that are widely expressed in the central nervous system [8]. Activation of α-7nAChR was associated with the stimulation of the survival phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) signaling pathway, which promotes translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus [9]. Nrf2 activation promotes the overexpression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1) reducing oxidative stress and inflammatory response [10]. It has also been suggested that α-7nAChR interacts with nuclear factor kappa B (NF-κB) and the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway suppressing the expression of inflammatory cytokines [11].

Tropisetron is a potent serotonin 5-HT3 receptor antagonist and a high affinity partial agonist at α-7nAChR [12]. The activation of α-7nAChR has been documented to inhibit various apoptotic and inflammatory signaling pathways with a subsequent neuroprotective potential [13]. Till now, no current approved treatments can hamper HD progression, although promising disease modifying treatments are being tested in animal models [1,14]. Based on this data, our study aimed to investigate the neuroprotective potential of tropisetron in 3-NP-induced HD in rats via activating α-7nAChR and to further explore the role of PI3K/Akt and JAK2/NF-κB trajectories.