Background/objectives: A water extract of the plant Centella asiatica (CAW) has been shown to improve cognitive deficits in aged mice when administered for 5 weeks in drinking water. However, the contribution of the constituent compounds within CAW to the beneficial effects of the extract remains unelucidated. This study evaluated the effects of triterpene (TT) and caffeoylquinic acids (CQA) found within CAW, on learning, cognitive flexibility, memory, and anxiety-like behaviors in aged C57BL6 mice. Methods: Eighteen-month-old male and female C57BL6 mice were administered either TT, CQA, or the combination (TT+CQA) in their drinking water for a total of 5 weeks, at concentrations corresponding to their presence in CAW. During the final two weeks of treatment learning, executive function, memory, and anxiety were assessed. Results: Aged mice of both sexes showed significant improvement in learning when treated with TT and CQA separately and in combination. Treatment with TT also improved cognitive flexibility in aged mice of both sexes, but CQA and the combination of TT+CQA did not alter cognitive flexibility in aged male mice. There was no effect on recognition memory or anxiety in any of the treatment groups (TT, CQA, TT+CQA) relative to mice treated with the vehicle control although there was a trend towards improved recognition memory with TT treatment. Conclusions: These results suggest that the TT and CQA present in CAW likely contribute to its previously reported amelioration of age-related cognitive changes, especially in learning and cognitive flexibility, while other constituents may be responsible for CAW’s anxiolytic effects.

Parkinson’s Disease (PD) is the second most diagnosed neurological disorder globally, affecting millions of people worldwide. Oxidative stress is implicated in the progression of PD, yet its direct effects on motor function, particularly in the context of synucleinopathy, are not fully understood. Here, we investigated the effects of the loss of the antioxidant regulatory transcription factor NRF2 in the A53TSyn mouse model of synucleinopathy. Motor function was evaluated in separate cohorts of A53TSyn mice without NRF2 (A53TSyn/NRF2KO), as well as A53TSyn mice expressing NRF2 (A53TSyn/NRF2+) and healthy wild-type (WT) mice at four, six, and eight months of age. The overall mobility decreased in A53TSyn/NRF2KO mice relative to WT mice at all ages. Significant alterations in gait were also apparent in A53TSyn/NRF2KO mice compared to A53TSyn mice without NRF2 deletion. Expression of tyrosine hydroxylase (TH) was also quantified in the brains of those mice. While there were no differences in cortical pSyn expression between A53TSyn/NRF2+ and A53TSyn/NRF2KO mice, a reduction in TH abundance in the striatum was evident in A53TSyn/NRF2KO mice at all ages. In summary, our data suggest that NRF2 plays a role in maintaining mobility and gait in the context of synucleinopathy and may represent a therapeutic target to mitigate mobility decline in PD-affected individuals.