ABSTRACT
Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3ß, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism.
Subject(s)
PPAR gamma , Propionates , Animals , Glycogen Synthase Kinase 3 beta , Nitro Compounds , PPAR gamma/metabolism , Pioglitazone/pharmacology , Propionates/toxicity , Rats , Telmisartan/pharmacologyABSTRACT
Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were split into four groups: vehicle control (0.2â¯ml/kg/48â¯h, sc), MK (10â¯mg/kg/day, ip), rotenone (1.5â¯mg/kg/48â¯h, sc.) and rotenone pretreated with MK. Rotenone treatment led to significant reduction in motor functioning and elevation in oxidative stress markers. Additionally, upregulation of p38 mitogen-activated protein kinase (p38 MAPK) and CysLT1 receptor expressions were anchored with enhanced striatal microglial activation generating a severe neuro-inflammatory milieu. Furthermore, an augmentation in p53 expression and cleaved caspases-3 activity increased apoptotic neurodegeneration synchronized with reduction of striatal tyrosine hydroxylase (TH) content. Changes in neuronal morphology was also noted. MK administration significantly mitigated motor impairment and rise in oxidative stress mediators. As well, the anti-inflammatory activity of MK was manifested by hindering the principal controller of inflammatory pathway, nuclear factor-kappa B, followed by its downstream pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta), by attenuating striatal microglial activation and hampering the expression of both p38 MAPK and CysLT1. Moreover, MK revealed a decline in p53 expression with its downstream cleaved caspases-3 which resulted in preservation of striatal TH terminals as verified by increased striatal TH content and improvement in the histopathological changes incited by rotenone. In conclusion, MK endowed neuroprotective effects in rotenone-induced PD animal model via attenuation of microglial cell activation and p38 MAPK expression.
