Authors:

Andrei Galatanu

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About Paper:

Postoperative cognitive dysfunction (POCD) is a significant clinical concern for elderly surgical patients. To investigate the mechanisms of this vulnerability, we sought to establish an accelerated aging phenotype in young adult mice using D-galactose (D-gal) and to evaluate the therapeutic potential of the a5-GABA-A receptor positive allosteric modulator, MP-III-002. Young adult male and female C57BL/6J mice (3 months old) were used across three experimental phases: Phase |: Oral D-gal (200 mg/kg/day) in drinking water for 8 weeks. Cognitive assessment included the Y-maze and trace contextual fear conditioning. Phase Il: Dose escalation to 400 mg/kg/day D-gal (oral) with the addition of MP-III-002 administered 2 days prior to and during behavioral testing (OFT, Y-maze, Fear Conditioning). Phase III (Double-Hit): Exploratory laparotomy was performed on 400 mg/kg D-gal-treated mice to model the interaction of oxidative stress and surgical trauma. In Phase |, 8-week D-gal treatment did not alter body weight. Interestingly, spatial working memory deficits in the Y-maze were observed exclusively in female mice, while no changes were found in fear conditioning for either sex. In Phase II, increasing the dose to 400 mg/kg (with or without MP-III-002) failed to produce significant deficits in fear conditioning or OFT. Notably, even the combination of surgical stress and high-dose oral D-gal (Phase III) did not replicate the cognitive impairment previously observed in our lab using naturally aged (18-month-old) or diphtheria toxin-induced "pseudo-old" mice with partially ablated somatostatin-positive interneurons in the dentate gyrus hilus. These findings suggest that oral administration of D-galactose in drinking water provides insufficient or inconsistent bioavailability to reliably model the aging-related cognitive decline necessary for POCD research in young adult C57BL/6J mice. Consequently, we are modifying our protocol to utilize chronic subcutaneous (s.c.) injection of D-galactose for 8 weeks to ensure systemic oxidative damage and a more robust aging phenotype.

Source:

University of Illinois Urbana-Champaign

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Co-authors:

Andrei Galatanu