Biology subjects

Gray, N. E.

Publications and source records attributed to Gray, N. E..

6 recordsLinked to original sources

bioRxiv2025

Centella asiatica improves sleep quality and quantity in aged mice

Age-related sleep disruption is common in older adults. Not only does the total amount of time spent in sleep decline, but the number of arousals during sleep increases with age. As sleep is important for both memory consolidation and to prevent neurodegenerative pathology, this decline in sleep and/or sleep consolidation may underlie age-related cognitive decline and dementias. Furthermore, treatment of sleep disruption can improve quality of life. However, few interventions have successfully reversed age-related sleep decline. Extracts from the plant Centella asiatica have demonstrated neuroprotective effects in human, rodent, and fly models of aging and neurodegenerative diseases, and is a promising intervention for dementias, yet little is known about how these extracts affect sleep patterns. Here, we administered Centella asiatica water extract (CAW) dosed or control chow to male and female C57BL6/J mice aged 18 months. Effects on sleep composition were determined using electrodes that recorded EEG and EMG signals. We found that CAW dosed chow (1000 mg/kg/day) increased REM sleep time in aged male mice and decreased the number of arousals during sleep observed in aged females, compared to age- and sex-matched controls. We conclude that CAW administered in food has a moderate, sex-dependent effect on sleep quantity and quality. Statement of SignificanceSleep declines with age and may underline age-related cognitive changes. However, few interventions have successfully reversed age-related sleep and cognitive decline. This study found that botanical extract from the plant Centella asiatica increased total REM sleep time in aged male mice, and decreased sleep fragmentation in aged female mice, compared to age- and sex-matched controls. Whether these moderate, sex-dependent effect sizes on sleep in aged mice are impactful enough to affect cognition, quality of life, and/or neurodegenerative pathology could be explored in future studies.

neuroscience↗

bioRxiv2024

Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica

BackgroundA water extract of the Ayurvedic plant Centella asiatica (CAW) improves cognitive function in mouse models of aging and Alzheimers disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plants therapeutic benefit. MethodsMouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively. ResultsExtensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level. ConclusionsFour gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.

neuroscience↗

bioRxiv2024

Asiatic acid improves mitochondrial function, activates antioxidant response in the mouse brain and improves cognitive function in beta-amyloid overexpressing mice.

Extracts of the plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on brain mitochondrial function, antioxidant response and cognition in healthy mice and a single concentration of AA in the beta-amyloid overexpressing 5xFAD mouse line. Associative memory and overall activity were assessed. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. In the 5xFAD line, total beta-amyloid plaque burden after AA treatment was also evaluated. In healthy mice, we report dose responsive effects of increasing concentrations of AA on enhanced associative memory and a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the highest AA dose (1% AA) were similar to what was observed with CAW. The high AA dose was then evaluated in the context of A{beta} accumulation in 5xFAD mice. Improvements in mitochondrial and antioxidant response genes were favored in females over males without significant alleviation of A{beta} plaque burden.

neuroscience↗

bioRxiv2024

The CD74 inhibitor DRhQ improves cognition and mitochondrial function in 5xFAD mouse model of Aβ accumulation

Neuroinflammation and mitochondrial dysfunction are early events in Alzheimers disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T-cell and macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here we evaluate its effects in {beta}-amyloid (A{beta}) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 {micro}g) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. A{beta} plaque burden in 5xFAD animals were not robustly impacted by DRhQ treatment nor was microglial activation, although in the hippocampus there was some evidence of a reduction in female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation as well as to optimize the dose, and timing of DRhQ treatment and gain a better understanding of its mechanism of action.

neuroscience↗

bioRxiv2024

Amelioration of age-related cognitive decline and anxiety in mice by Centella asiatica extract varies by sex, dose and mode of administration.

We have previously reported that a water extract (CAW) of the Ayurvedic plant Centella asiatica administered in drinking water can improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here we compared the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice. Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.2, 0.5 or 1% w/w) to provide 0, 200 mg/kg/d, 500 mg/kg/d or 1000 mg/kg/d for a total of 5 weeks. An additional group of eighteen-month-old mice were treated with CAW (10 mg/mL) in their drinking water for a total of five weeks to deliver the same exposure of CAW as the highest dietary dose (1000 mg/kg/d). CAW doses delivered were calculated based on food and water consumption measured in previous experiments. In the fourth and fifth weeks, mice underwent behavioral testing of cognition, anxiety and depression (n=12 of each sex per treatment group in each test). Aged mice of both sexes showed cognitive deficits relative to young mice while only female aged mice showed increased anxiety compared to the young female mice and no differences in depression were observed between the different ages. CAW (1000 mg/kg/d) in the drinking water improved deficits in aged mice in learning, executive function and recognition memory in both sexes and attenuated the increased measures of anxiety observed in the aged female mice. However, CAW in the diet only improved executive function in aged mice at the highest dose (1000 mg/kg/d) in both sexes and did so less robustly than when given in the water. There were no effects of CAW on depression-like behavior in aged animals regardless of whether it was administered in the diet or the water. These results suggest that CAW can ameliorate age-related changes in measures of anxiety and cognition and that the mode of administration is important for the effects of CAW on resilience to these age-related changes.

animal behavior and cognition↗

bioRxiv2023

Gardenin A improves cognitive and motor function in A53T-α-syn mice

Oxidative stress and neuroinflammation are widespread in the Parkinsons disease (PD) brain and contribute to the synaptic degradation and dopaminergic cell loss that result in cognitive impairment and motor dysfunction. The polymethoxyflavone Gardenin A (GA) has been shown to activate the NRF2-regulated antioxidant pathway and inhibit the NFkB-dependent pro-inflammatory pathway in a Drosophila model of PD. Here, we evaluate the effects of GA on A53T alpha-synuclein overexpressing (A53TSyn) mice. A53TSyn mice were treated orally for 4 weeks with 0, 25, or 100 mg/kg GA. In the fourth week, mice underwent behavioral testing and tissue was harvested for immunohistochemical analysis of tyrosine hydroxylase (TH) and phosphorylated alpha synuclein (pSyn) expression, and quantification of synaptic, antioxidant and inflammatory gene expression. Results were compared to vehicle-treated C57BL6 mice. Treatment with 100 mg/kg GA improved associative memory and decreased abnormalities in mobility and gait in A53TSyn mice. GA treatment also reduced cortical and hippocampal levels of pSyn and attenuated the reduction in TH expression in the striatum. Additionally, GA increased cortical expression of NRF2-regulated antioxidant genes and decreased expression of NFkB-dependent pro-inflammatory genes. GA was readily detectable in the brains of treated mice and modulated the lipid profile in the deep gray brain tissue of those animals. While the beneficial effects of GA on cognitive deficits, motor dysfunction and PD pathology are promising, future studies are needed to further fully elucidate the mechanism of action of GA, optimizing dosing and confirm these effects in other PD models. Significance StatementThe polymethoxyflavone Gardenin A can improve cognitive and motor function and attenuate both increases in phosphorylated alpha synuclein and reductions in tyrosine hydroxylase expression in A53T alpha synuclein overexpressing mice. These effects may be related to activation of the NRF2-regulated antioxidant response and downregulation of NFkB-dependent inflammatory response by Gardenin A in treated animals. The study also showed excellent brain bioavailability of Gardenin A and modifications of the lipid profile, possibly through interactions between Gardenin A with the lipid bilayer, following oral administration. The study confirms neuroprotective activity of Gardenin A previously reported in toxin induced Drosophila model of Parkinsons disease.

neuroscience↗