Basic Science and Pathogenesis.

Background: Our previous studies reported that D-galactose (D-gal) administration for four to eight weeks caused metabolic disturbance, brain mitochondrial dysfunction, and brain aging, leading to cognitive dysfunction in similar with natural aging condition. Spermidine is a polyamine that can be found naturally. Spermidine has been showed the beneficial effects on various models, such as attenuating metabolic/gut impairments in obesity, and ameliorating memory loss in aged model. However, those beneficial effects of spermidine in D-galactose-induced aging condition is still unclear.

Method: Eighteen female Wistar rats were divided into two groups which received either NSS as a control group (n = 6) or D-gal (150 mg/kg/day, n = 12), subcutaneously for total twenty weeks. At week 12, D-gal-treated rats were divided into two subgroups; NSS as a vehicle and spermidine (20 mg/kg/day), orally for 8 weeks (n = 6 per subgroup). At the end of protocol, the cognitive tests; novel object location (NOL) and novel object recognition (NOR) were performed. After animals were euthanized, brain/gut tissues and blood samplings were collected to determine the biochemical parameters.

Result: Systemic/gut oxidative stress by increasing the serum malondialdehyde (MDA) level and attenuating colon SOD2 protein expression respectively were shown in D-gal-treated rats (Figure 1A-B). Levels of colon ZO-1 mRNA was decreased in D-gal-treated rats, in comparison to control group (Figure 1C). Upregulation of hippocampal senescence-associated b-galactosidase (SA-b-gal), elevation of brain mitochondrial ROS level, and cognitive impairment by reducing the percentage of preference index of NOL and NOR were also observed in D-gal-treated rats (Figure 1D-E, G-H). Interestingly, spermidine treatment in D-gal-treated rats alleviated serum MDA and upregulated colon SOD2 protein levels, compared to D-gal-treated rats with vehicle (Figure 1A-B). Spermidine also reduced hippocampal SA-b-gal protein expression, decreased brain mitochondrial ROS level and swelling (Figure 1D-F), and attenuated the learning and memory impairment by restoring the percentage of preference index of NOL and NOR in D-gal-treated rats (Figure 1G-H).

Conclusion: Our findings suggest that spermidine exerts the beneficial effects on cognition through reducing systemic/brain oxidative stress in D-galactose-induced aging rats. Therefore, it is possible that spermidine should be considered as a novel therapeutic option for ameliorating neuropathology in aging condition.