Valsartan repurposing to mitigate autoimmune encephalomyelitis via ACE2/Ang1-7/MasR axis pathway cognitive and...

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Multiple sclerosis (MS) is a neuroinflammatory disease causing cognitive impairment.
• The renin-angiotensin system (RAS) is a potential therapeutic target for neurodegenerative cognitive deficits.

Purpose of the Study:

• To investigate valsartan's (VAL) effects on cognitive function in an experimental autoimmune encephalomyelitis (EAE) mouse model.
• To explore VAL's impact on ACE2/Ang 1-7/MasR signaling and the PI3K/Akt/CREB/BDNF pathway in preserving cognition.

Main Methods:

• EAE was induced in mice; cognitive function was assessed using novel object recognition (NOR) and Morris water maze (MWM).
• Histological analysis, bioinformatics, and chemo-bioinformatics were employed to elucidate molecular mechanisms.
• VAL was administered orally at 40 mg/kg/day.

Main Results:

• VAL treatment significantly improved spatial and learning memory in EAE mice, reducing clinical scores and demyelination.
• VAL activated the ACE2/Ang 1-7/MasR pathway, leading to increased p-PI3K/p-Akt/p-CREB and BDNF signaling.
• VAL reduced neuroinflammation (p-NFκB p65, TNF-α, IL-6) and restored redox balance (SOD, GPx, GSH, MDA).

Conclusions:

• Valsartan shows potential in preserving cognitive function in MS by modulating neuroprotective and anti-inflammatory pathways.
• Targeting the ACE2/Ang 1-7/MasR and BDNF pathways offers a promising therapeutic strategy for MS-related cognitive deficits.
• These findings support VAL as a potential therapeutic agent for neuroinflammatory disorders affecting cognition.