Neuroprotective Potential of NR in Ameliorating CCH-Induced Cognitive Impairment
Introduction
Chronic cerebral hypoperfusion (CCH) has been identified as one of the initial conditions critical to the development of cognitive impairment, which is tightly associated to the complex neurological disorders such as Alzheimer's disease and vascular dementia (VaD). Currently, there is a multitude of research studies focused on the treatment of Alzheimer's disease, but there are still no effective treatment options available for CCH-related VaD. Notably, nicotinamide riboside (NR), a precursor of NAD+, can ameliorate CCH-related VaD, exerting a neuroprotective effect.About CCH
CCH refers to a pathological state of the nervous system caused by an enduring inadequate blood flow to the brain. In traditional Chinese medicine, CCH belongs to the categories of dizziness, headache, amnesia, sleepless, somnolence and depression. The prominent pathophysiological mechanisms of CCH involve mitochondrial degeneration, disturbed energy metabolism, cellular autophagy and apoptosis, oxidative stress, neuronal inflammation/damage, etc.Restoration of pathological structure in CCH rats post NR treatment
Mitochondria in the CCH group exhibit noticeable structural abnormalities, such as swelling and broken or disappearing cristae. In contrast, mitochondria in the Sham and NR treatment groups display prominent cristae and intact membranes, restoring the mitochondrial structure to a normal state.
Meanwhile, potential pathomorphological changes and neuronal damage are observed in CCH group, as manifested by an increase in deeply stained areas and a reduction in the number of normal neurons. Yet, NR counteracts these morphological changes and increases the number of neurons in the CA1 and CA3 regions of the hippocampus.
Therapeutic promise of NR in CCH rats
As an NAD+ booster, NR is capable of raising blood and brain NAD+ levels, improving cortical blood oxygen saturation (T2* values), enhancing cognitive function, and reducing neuropathological damage in rats with CCH. Specifically, it significantly improves CCH-induced spatial referencing, learning, and memory deficits. Meanwhile, it also reduces hippocampal neuronal loss and abnormalities and mitigates the decrease in dendritic spine density. Moreover, NR alleviates CCH-induced mitochondrial injury by regulating mitochondrial fission (Drp1 ↓) and autophagy impairment (P62 ↓, LC3B-II ↓).
