Creatine Supplementation Upregulates mTORC1 Signaling and Markers of Synaptic Plasticity in the Dentate Gyrus While Ameliorating LPS-Induced Cognitive Impairment in Female Rats

Abstract

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.

Selective breeding for physical inactivity produces cognitive deficits via altered hippocampal mitochondrial and synaptic function

“…To test spatial memory, a gray Barnes maze circular platform (122 cm in diameter) with 20 holes (each being 10.2 cm in diameter) was used similarly to our previous publications ( Kelty et al, 2019 ; Mao et al, 2021 ). Briefly, the circular platform contained an escape box (28 cm in length, 12.7 cm width, 7.6 cm height) located such that the rat could climb down and in.…”

“…cDNA from each sample was assayed in duplicate for the target genes in Table 1 using iTaq Universal SYBR green Supermix (Bio-Rad Laboratories, Hercules, CA). mRNA expression values were quantified by the 2 (−delta delta CT) (Kelty et al, 2019(Kelty et al, , 2022Grigsby et al, 2020;Mao et al, 2021) method normalized to Pgk1.…”

The role of creatine supplementation and mTORC1 signaling in ameliorating cognitive deficiency in a neuroinflammatory rat model

“…Creatine (Cr), an ergogenic aid for professional athletes and bodybuilders, was proved to be cognitively beneficial under various pathologies and disorders [81]- [83], [86], [89], [90]. In our previous publication [165], 6 weeks of Cr supplementation was found to significantly ameliorate the spatial and recognition memory deficits caused by neuroinflammation in female Wistar rats.…”

“…A transitional state namely mild cognitive impairment (MCI) representing a stage of cognitive function between normal aging and dementia existed, at which it was supported as a therapeutic window for early treatment [162], [163]. Previous studies [136], [164], [165], including our own, utilized animal models to mimic MCI have discovered promising future interventions for ameliorating cognitive impairment. As such, an in-depth understanding of underlying neuro-molecular mechanisms is required for future clinical trials.…”

“…Based upon our previous findings [165], the present study aimed to test the role of mTORC1 signaling during the amelioration of cognitive impairment caused by Cr supplementation. For doing this, intracerebroventricular (i.c.v.)…”