Abstract
N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D-serine, synthesized from L-serine by a pyridoxal 5′-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L-serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 μg/10 μL) and LEHA (100 μg/10 μL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 μg/10 μL of D-serine were injected intrathecally. Since no in vivo results have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain.
Highlights
D-serine, a coagonist of the glycine site of the N-methyl-D-aspartic acid receptor (NMDAr), have been involved in many neurodegenerative disorders, in which pathological overactivation of the receptor results in neurotoxicity, as revealed by studies performed in cell cultures and observed in the Alzheimer disease
We have studied the effect of two compounds that were able to reduce the activity of the serine racemase in vitro or in cell cultures
It can be observed that the C-response either in normal or monoarthritic rats is constant and the C-reflex paradigm is unaffected by the both treatments
Summary
D-serine, a coagonist of the glycine site of the NMDAr, have been involved in many neurodegenerative disorders, in which pathological overactivation of the receptor results in neurotoxicity, as revealed by studies performed in cell cultures and observed in the Alzheimer disease. In serine racemase KO mice (SR-KO), around 90% decrease in forebrain D-serine content has been observed, and in parallel, a reduced neurotoxicity induced by both NMDA and β-Amyloid forebrain SR-KO mice injection was found. Microglia culture cells exposed to amyloid β-peptide as a proinflammatory stimuli elicited a release of glutamate This activated microglia express SR, and thereby release D-serine, contributing to the neurotoxicity found in inflammatory conditions in the brain, and in the Alzheimer’s disease where SR RNA was elevated [2]. Regarding D-serine degradation, it is performed by the D-amino acid oxidase, contributing to the D-serine homeostasis [3] Another mechanism proposed to be responsible of D-serine modulation is gated by NMDAr activation, promoting the translocation of SR to the plasma membrane, reducing enzyme activity [4]. The authors found that the degradation of L-serine-O-sulfate (to pyruvate and ammonia) was two or three orders of magnitude faster
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