ABSTRACT
OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation (LTP) and cognitive impairment induced by stress or corticosterone. However, other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment. The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms. METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation (HFS) to induce LTP impairment. NMDA receptor antagonists and agonists were administrated by icv. RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice. Corticosterone increased the gluta?mate level in hippocampal tissues, neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP, while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone, suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticoste?rone. Further results showed that the level of D-serine and its precursor L-serine did not change. D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1 (ASC-1) in the cell membrane was decreased and increas?ing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticoste?rone. CONCLUSION Taken together, this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction, which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.
ABSTRACT
As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate and activity of d-serine alone and in combination with -lactams against methicillin-resistant (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, -lactams alone and in combinations was evaluated both by standard MICs, time-kill curves and checkerboard assays, and by murine systemic infection model as well as neutropenic thigh infection model. An synergistic effect was demonstrated with the combination of d-serine and -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to -lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with -lactams against MRSA strains both and . Considering the relatively good safety of d-serine alone or in combination with -lactams, d-serine is worth following up as new anti-MRSA infection strategies.
ABSTRACT
La gabapentina es un agente útil para el alivio de la neuralgia del trigémino y el dolor orofacial fantasma. Sin embargo, existe poca información sobre el efecto antinociceptivo de la gabapentina en los modelos de dolor orofacial. En este trabajo se investigó el efecto antinociceptivo de la gabapentina sobre el acicalado facial en la rata, provocado por la inyección de la formalina, un paradigma de dolor orofacial. La dosis de 10 mg/kg IP de la gabapentina produjo una drástica disminución del acicalado facial en la fase I y II indicando un claro efecto antinociceptivo. Sin embargo, en la dosis de 1 mg/kg IP, la gabapentina tuvo un efecto antinociceptivo sólo en la fase I. La D-serina (100 µg, ICV) no produjo efecto inyectada sola y no antagonizó el efecto antinociceptivo de la gabapentina. Por el contrario, la combinación de la gabapentina-1 mg/kg IP más D-serina redujo significativamente el acicalado facial en la fase II. Este resultado muestra una diferencia con estudios en que la gabapentina induce antinocicepción en la prueba de la formalina en la pata de la rata sólo en la fase II y la D-serina antagoniza a la gabapentina. Los resultados se discuten en relación al proceso de dolor en la pata posterior versus la estimulación dolorosa orofacial.
Gabapentin is a useful agent for the relief of trigeminal neuralgia and orofacial phantom pain. However, there is scarce information on the gabapentin analgesic effect in orofacial pain models. We tested the analgesic action of gabapentin on the formalin-induced face grooming in the rat, an orofacial pain paradigm. IP Gabapentin (10 mg/kg), induced a drastic reduction in face grooming during phase I and II, indicating a clear-cut antinociceptive effect. However, at 1 mg/kg, gabapentin had an analgesic effect only on phase I. D-serine (100 µg, ICV) was silent when given alone and did not antagonize the antinociceptive effect of gabapentin. On the contrary, gabapentin 1 mg/kg plus D-serine significantly reduced face grooming in phase II. These results show a difference between gabapentin induced orofacial analgesia and previous studies showing gabapentin-induced hind paw analgesia in the formalin test, only during phase II, as well as D-serine antagonism of gabapentin. The results are discussed in terms of different pain processing of hind paw, versus orofacial nociceptive stimulation.
Subject(s)
Animals , Rats , Analgesics/therapeutic use , Pain Measurement/methods , Facial Pain/therapy , Trigeminal Neuralgia/therapyABSTRACT
D-amino acids were believed to have no function in higher organisms several years ago. Recently, D-serine was proved to be synthesized by astrocytes in vivo and be released to work as an effective coagonist at the “glycine-binding” site of the N-methyl-D-aspartate (NMDA) glutamate receptors in central nervous system. In this paper, the synthesis, metabolism and function of D-serine were reviewed briefly.
ABSTRACT
BACKGROUND: Previous reports have described NMDA antagonist reduced the nerve injury induced or inflammatory thermal hyperalgesia. One of the peculiarities of the NMDA receptor is the requirement for glycine as the co-agonist in order to be activated. Thus, the function of NMDA receptors can be modulated by ligands acting as agonists or antagonists at the glycine co-agonist site. ACEA 1021 has been recently characterized as a high potency competitive NMDA receptor/glycine site antagonist. This study evaluated the effects of spinally administered ACEA 1021 on the thermal hyperalgesia state induced by mild burn. METHODS: Rats were prepared with chronic spinal catheters. A thermal injury was induced after briefly anesthetizing with halothane, by applying the left hind paw to a thermal surface (52.5oC) for 45 sec. This exposure results in a mild erythema, but no blistering. Thermal escape latency of the hind paw was determined using an underglass thermal stimulus with which response latencies of the injured and uninjured (normal) paw could be obtained. In this work, ACEA 1021 was injected through intrathecal catheters in rats with mild burn injury on the right hindpaw, after then paw withdrawal latency was measured in both hindpaw every 30 minute for 3 hours. RESULTS: The intrathecal injection of ACEA 1021 (2.4-24 microgram) produced a dose dependent reversal of the hyperalgesia in the right hindpaw, but had no effect upon the response latency of the normal left hind paw even at the largest doses. The effects of intrathecal ACEA 1021 on the hyperalgesia reversed by intrathecal D-serine. CONCLUSIONS: Intrathecal ACEA 1021, competitive-glycine site NMDA receptor antagonist produce a dose-dependent inhibition and D-serine-sensitive reversal of the thermal hyperalgesia evoked mild burn injury. These results suggested that the glycine site of spinal NMDA receptor play an important role in the hyperalgesia induced by mild burn injury.