NMDA Receptor Hypofunction in the Aging-Associated Malfunction of Peripheral Tissue

Abstract

Glutamatergic transmission through NMDA receptors (NMDARs) is important for the function of peripheral tissues. In the bone, NMDARs and its co-agonist, D-serine participate in all the phases of the remodeling. In the vasculature, NMDARs exerts a tonic vasodilation decreasing blood perfusion in the corpus cavernosum and the filtration rate in the renal glomerulus. NMDARs are relevant for the skin turnover regulating the proliferation and differentiation of keratinocytes and the formation of the cornified envelope (CE). The interference with NMDAR function in the skin leads to a slow turnover and repair. As occurs with the brain and cognitive functions, the manifestations of a hypofunction of NMDARs resembles those observed during aging. This raises the question if the deterioration of the glomerular vasculature, the bone remodeling and the skin turnover associated with age could be related with a hypofunction of NMDARs. Furthermore, the interference of D-serine and the effects of its supplementation on these tissues, suggest that a decrease of D-serine could account for this hypofunction pointing out D-serine as a potential therapeutic target to reduce or even prevent the detriment of the peripheral tissue associated with aging.

Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation

“…We found that D-serine supplementation decreases the number of perseverative errors in a reversal learning task in middle-aged and aged rats by increasing the functional connectivity between frontal association areas with retrosplenial and cingulate cortex. Furthermore, D-serine supplementation did not induce nephrotoxicity; instead, it restored the thickness of the epithelial tissue in the straight portion of proximal renal tubules of senescent rats suggesting that D-serine can reverse the detriment of aging-associated malfunction of peripheral tissue ( Rivera-Villaseñor et al, 2021 ). D-serine did not improve cognitive flexibility in young rats showing that D-serine effect is age-dependent pointing to a possible intervention in restoring the levels of D-serine to reverse cognitive functions that are affected in the aged brain.…”

Promising applications of D-amino acids in periprosthetic joint infection

“…However, the mechanisms for this remain elusive. Rivera-Villasenor et al 296 further theorized that the expression of NMDA receptors on early osteoblasts decreases with increasing age, which may subsequently inhibit osteoblast maturation. The authors speculated that this would result in a secondary decrease in D-Ser release by mature osteoblasts, thereby promoting osteoclast maturation, bone resorption, and potentially progressing age-associated osteoporosis.…”

“…302 D-Asp is also likely involved in aging of the skin and the development of arthrosclerosis, macular degeneration, and cataracts. 296,299,303 To this end, several D-AAs have been identified in human lenses in the eye, including D-Asp, D-Ser, D-Glu/Gln, and D-Phe, where the amount of racemization of D-Ser and D-Asp was significantly increased in cataract lenses when compared with age-matched healthy lenses. 304 In terms of cancer and tumor growth, D-AAs appear to display a varied response dependent on tumor etiology and condition.…”

“…Sanchez et al 197 demonstrated that D-Phe, D-Pro, D-Met, 144 • Inhibition of bacterial adhesion to eukaryotic cells 145,174 • Secreted by osteoblast. Modulates osteoblast maturation and osteoclastogenesis in bone 295,296 • Neurotransmission. Regulation of N-methyl-D-aspartate receptor activity 286 • Association with Alzheimer's disease [290][291][292] • Association with cataracts 304 • Association of high levels with kidney disease and impaired renal function 313,314 D-Tryptophan • Host immune evasion 150 • Inhibition of bacterial adhesion to abiotic surfaces 172 • Inhibition of biofilm formation 118,174,194,263 • Biofilm disassembly 194,197,245 • Inhibition of bacterial growth 118,174 • Modulation of bacterial virulence 174 • Promotion of bacterial motility (swimming and twitching) 263 • Inhibition of bacterial adhesion to eukaryotic cells 174 • Increased bone density, volume, trabecular thickness, and reduced osteoclastic activity in vivo 196 • Reduced S. aureus-induced abnormal bone remodeling 196 • No adverse bone tissue response in a rat segmental defect model in vivo 194 • Eukaryotic cell protection from cell death in bacterial infections 174…”

The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice

“…NMDARs have effects on multiple organs outside of the central nervous system [ 24 ]. Penile neuronal NOS, GluN1, and GluN2 NMDAR subunits are expressed in the cavernosal nerves of the corpus cavernosum and are frequently colocalized [ 25 , 26 ]. However, the role of NMDAR in corpus cavernosum is not well defined.…”