Long-term gabapentin treatment impairs cognitive function in aged mice via tau hyperphosphorylation

Area of Science:

• Neuroscience
• Gerontology
• Pharmacology

Background:

• Gabapentin (GBP) is frequently prescribed for pain in older adults.
• Recent evidence suggests GBP negatively impacts cognitive function in the elderly.
• The precise molecular mechanisms of GBP's cognitive effects in aging remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms behind gabapentin's adverse effects on cognitive function in aged individuals.
• To explore the role of Sirt1 and tau phosphorylation in gabapentin-induced cognitive impairment.
• To assess potential therapeutic strategies targeting Sirt1 to mitigate gabapentin's side effects.

Main Methods:

• Aged mice underwent spared nerve injury (SNI) or sham surgery and received gabapentin (GBP) treatment.
• Cognitive function was evaluated using novel object recognition (NOR) and fear conditioning tests (FCT).
• Hippocampal tissues were analyzed for p-tau, CaMKIIα, and Sirt1 levels; gene overexpression via AAV was employed.

Main Results:

• Long-term GBP treatment impaired learning and memory in aged mice, irrespective of pain status.
• GBP treatment led to increased hippocampal p-tau (S416, S262) and CaMKIIα, with decreased Sirt1 expression.
• Sirt1 overexpression or resveratrol administration reversed GBP-induced cognitive deficits and tau hyperphosphorylation.

Conclusions:

• Long-term gabapentin administration detrimentally affects cognitive function in aged mice.
• GBP suppresses Sirt1, increasing CaMKIIα and tau hyperphosphorylation, contributing to memory impairment.
• Enhancing Sirt1 activity effectively counteracts gabapentin's negative cognitive effects in aging.