Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

Abstract

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. Injection of 3-nitropropionic acid (3-NP) is a widely used experimental model for induction of HD. The current study aimed to inspect the potential neuroprotective properties of azilsartan (Azil), an angiotensin II type 1 receptor blocker (ATR1), in 3-NP-induced striatal neurotoxicity in rats. Rats were randomly allocated into five groups and treated for 14 days as follows: group I received normal saline; group II received Azil (10 mg/kg, p.o.); group III received 3-NP (10 mg/kg, i.p); group IV and V received Azil (5 or 10 mg/kg, p.o, respectively) 1 h prior to 3-NP injection. Both doses of Azil markedly attenuated motor and behavioural dysfunction as well as striatal histopathological alterations caused by 3-NP. In addition, Azil balanced striatal neurotransmitters levels as evidenced by the increase of striatal gamma-aminobutyric acid content and the decrease of glutamate content. Azil also amended neuroinflammation and oxidative stress via modulating IĸB/NF-ĸB and KEAP1/Nrf2 downstream signalling pathways, as well as reducing iNOS and COX2 levels. Moreover, Azil demonstrated an anti-apoptotic activity by reducing caspase-3 level and BAX/BCL2 ratio. In conclusion, the present study reveals the neuroprotective potential of Azil in 3-NP-induced behavioural, histopathological and biochemical changes in rats. These findings might be attributed to inhibition of ATR1/NF-κB signalling, modulation of Nrf2/KEAP1 signalling, anti-inflammatory, anti-oxidant and anti-apoptotic properties. Graphical Abstract

Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications

“…Restored striatal GABA and glutamate levels in the treated rats [161] Silyl resveratrol derivatives 3-NP-induced HD mice 20 mg/kg was administered intraperitoneally for 2 weeks (avoiding weekends) after disease onset (day 12 post-immunization), and data was collected for 7 weeks.…”