Chronic systemic D‐galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: Protective effects of R‐α‐lipoic acid

Abstract

Chronic systemic exposure of D-galactose to mice, rats, and Drosophila causes the acceleration of senescence and has been used as an aging model. However, the underlying mechanism is as yet unclear. To investigate the mechanisms of neurodegeneration in this model, we studied cognitive function, hippocampal neuronal apoptosis and neurogenesis, and peripheral oxidative stress biomarkers and also the protective effects of the antioxidant R-alpha-lipoic acid. Chronic systemic exposure of mice to D-galactose (100 mg/kg, s.c., 7 weeks) induced a spatial memory deficit, an increase in cell karyopyknosis, apoptosis, and caspase-3 protein levels in hippocampal neurons, a decrease in the number of new neurons in the subgranular zone in the dentate gyrus, a reduction of migration of neural progenitor cells, and an increase in death of newly formed neurons in the granular cell layer. The D-galactose exposure also induced an increase in peripheral oxidative stress, including an increase in malondialdehyde and decreases in total antioxidative capabilities (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus and also reduced peripheral oxidative damage by decreasing malondialdehyde and increasing T-AOC and T-SOD, without an effect on GSH-Px. These findings suggest that chronic D-galactose exposure induces neurodegeneration by enhancing caspase-mediated apoptosis and inhibiting neurogenesis and neuron migration, as well as increasing oxidative damage. In addition, D-galactose-induced toxicity in mice is a useful model for studying the mechanisms of neurodegeneration and neuroprotective drugs and agents.

Improving Effect of Silk Peptides on the Cognitive Function of Rats with Aging Brain Facilitated by D-Galactose

“…During aging, brain atrophy and malfunction of cholinergic nervous system occur, leading to cognitive defi cit. Facilitated brain aging by only 4-week injection of D -Gal (150 mg/kg) caused reduction of ACh concentration in CSF to lower than 55% of control level, brain damage/aging (increase in activated astrocytes to 1.7 times), and severe learning and memory dysfunction (Cui et al, 2006;Lei et al, 2008;Kumar et al, 2010).…”

“…Biomol Ther 19(2), 224-230 (2011) www.biomolther.org www.biomolther.org infl ammatory brain injury through activation and degeneration of astrocytes, but also causes cognitive defi cits by activating acetylcholinesterase (AChE), an ACh-degrading enzyme (Cui et al, 2006;Lei et al, 2008;Kumar et al, 2010). Accordingly, in the present study, we adopted D -Gal as a model compound for facilitated brain aging.…”

D-Galactose Induces a Mitochondrial Complex I Deficiency in Mouse Skeletal Muscle: Potential Benefits of Nutrient Combination in Ameliorating Muscle Impairment

“…8 At the eighth week following the start of D-gal administration, the animals' spatial memory was assayed by the MWM.…”

“…Although some researchers have challenged the D-gal-induced aging model, 2,3 some other researchers indicate that D-gal-treated animals showed some hallmarks of aging, such as a shortened lifespan, 4 cognitive dysfunction, 5 presbycusis, 6 increased oxidative stress, 4,7 decreased antioxidant enzyme activity, 8 diminished immune responses, 9 increased advanced glycation endproducts, 10 accumulation of mitochondrial DNA mutations, 11 and mitochondrial dysfunction. 5,12 Mitochondria are not only the major sites of intracellular reactive oxygen species (ROS) production, but also targets of ROS.…”

Isochaihulactone protects PC12 cell against H2O2 induced oxidative stress and exerts the potent anti-aging effects in D-galactose aging mouse model

“…D-galactose was converted into galactitol, which is not metabolized by above enzymes but accumulate in the cell, that leads to osmotic stress and ROS production [21] . In addition, supplementation with antioxidants has been reported to be beneficial with respect to slowing the aging process [22,23] .…”