Telmisartan neuroprotective effects in 3-nitropropionic acid Huntington's disease model in rats: Cross talk between PPAR-γ and PI3K/Akt/GSK-3β pathway

Huntington's disease (HD) is an inherited devastating neurodegenerative disorder with disabling motor and cognitive derangements that hinder the patients from performing their daily activities.

Aims: The present study was carried out to investigate telmisartan-induced neuroprotection against 3-nitropropionic acid (3-NP) model of HD in rats.

Main methods: Telmisartan was administered orally with a dose of 10 mg/kg/day, 1 h prior to 3-NP (10 mg/kg/day, i.p) for 14 days.

Key findings: 3-NP-injected animals which were treated with telmisartan showed marked improvement in muscle strength and motor functions evaluated by rotarod, grip strength, and open field tests. Moreover, administration of telmisartan attenuated 3-NP-induced oxidative stress, neuro-inflammation, and apoptosis with prominent decline in malondialdehyde striatal content in addition to NADPH oxidase reduced expression contrary to noticeable increment in reduced glutathione content. Additionally, the pro-inflammatory markers; tumor necrosis factor-α, interleukin-1β, prostaglandin E2, and cyclooxygenase-2 contents were significantly reduced along with decreased active caspase-3 immunoreactivity. Telmisartan was also implicated in the modulation of phosphatidyl inositol 3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/Akt/GSK-3β) and extracellular signal-regulated kinase (ERK) 1/2 cascades with consequent anti-oxidative, anti-inflammatory, and anti-apoptotic effects. Photomicrographs of telmisartan-treated animals confirmed its neuroprotective effects showing dismounted neuronal death and obvious increase in neuronal survival. These beneficial effects could be attributed to telmisartan's ability to induce peroxisome proliferator activated receptor-γ expression as well as its well-known blocking effect of angiotensin-II receptors type 1.

Significance: Subsequently, telmisartan is deemed as a promising candidate for HD management.