Inhibition of the NMDA receptor protects the rat sciatic nerve against ischemia/reperfusion injury

Abstract

Inhibition of the N-methyl-D-aspartate (NMDA) receptor by MK-801 reduces ischemia/reperfusion (I/R) injury in the central nervous system. However, few previous studies have evaluated the neuroprotective effects of MK-801 against peripheral I/R injury. The present study aimed to investigate the protective effects of MK-801 pretreatment against I/R injury in the rat sciatic nerve (SN). Sprague-Dawley rats were subjected to a sham surgery (n=8) or to a 5-h ischemic insult by femoral artery clamping (I/R and I/R+MK-801 groups; n=48 per group). I/R+MK-801 rats were intraperitoneally injected with MK-801 (0.5 ml or 1 mg/kg) at 15 min prior to reperfusion. The rats were sacrificed at 0, 6, 12, 24, 72 h, or 7 days following reperfusion. Plasma malondialdehyde (MDA) and nitric oxide (NO) concentrations, and SN inducible NO synthase (iNOS) protein expression levels, were measured using colorimetry. In addition, the protein expression levels of tumor necrosis factor-α (TNF-α) were measured using immunohistochemistry, and histological analyses of the rat SN were conducted using light and electron microscopy. Alterations in the mRNA expression levels of TNF-α and TNF-α converting enzyme (TACE) in the rat SN were detected using reverse transcription-quantitative polymerase chain reaction. In the I/R group, plasma concentrations of NO (175.3±4.2 µmol/l) and MDA (16.2±1.9 mmol/l), and the levels of iNOS (2.5±0.3) in the SN, peaked at 24 h post-reperfusion. At 24 h, pretreatment with MK-801 significantly reduced plasma NO (107.3±3.6 µmol/l) and MDA (11.8±1.6 mmol/l), and SN iNOS (1.65±0.2) levels (all P<0.01). The mRNA expression levels of TNF-α and TACE in the SN were significantly reduced in the I/R+MK-801 group, as compared with the I/R group (P<0.05). Furthermore, MK-801 pretreatment was shown to have alleviated histological signs of I/R injury, including immune cell infiltration and axon demyelination. The results of the present study suggested that pretreatment with MK-801 may alleviate I/R injury of the SN by inhibiting the activation of TNF-α and reducing the levels of iNOS in the SN.

The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning—Effects on Heart Function and Oxidative Stress

“…As well as the beneficial role of NO in the regulation of vascular reactivity in a prooxidant environment such as I/R, the inducible form of NOS (iNOS) is activated leading to increased production of O 2 − [53]. Due to this fact it was shown that MK-801 decrease I/R injury of sciatic nerve by decrease of oxidative damage and activity of iNOS [54]. Furthermore, given that vascular smooth muscle cells (VSMC) also express NMDARs, it was shown that Hcy, as an NMDAR activator, may induce the production of C-reactive protein (CRP) and oxidative stress, while MK-801 prevented such changes [55].…”

Resveratrol alleviates nuclear factor‐κB‐mediated neuroinflammation in vasculitic peripheral neuropathy induced by ischaemia–reperfusion via suppressing endoplasmic reticulum stress

“…Inducing IR in the nerve nutrient vessels can induce an inflammatory response in the neuronal microcirculatory environment which may cause a painful peripheral neuropathy that predisposes a person to chronic pain syndromes such as complex regional pain syndrome . Previous studies have reported that in nerves subjected to IR, there are releases of inflammatory mediators such as inducible nitric oxide synthase, intercellular adhesion molecule‐1, tumour necrosis factor‐α (TNF‐α) and NF‐κB .…”

“…In the present study, we evaluated the effects of resveratrol on be- Inducing IR in the nerve nutrient vessels can induce an inflammatory response in the neuronal microcirculatory environment which may cause a painful peripheral neuropathy that predisposes a person to chronic pain syndromes such as complex regional pain syndrome. [24][25][26][27] Previous studies have reported that in nerves subjected to IR, there are releases of inflammatory mediators such as inducible nitric oxide synthase, intercellular adhesion molecule-1, tumour necrosis factor-α (TNF-α) and NF-κB. 24,25 This concept has been confirmed by our previous study which demonstrated that VPN induced by IR in the rat femoral artery activates the transcription factor NF-κB as well as the pro-inflammatory cytokines TNF-α and interleukin-1β (IL-1β) in the sciatic nerve.…”

“…[24][25][26][27] Previous studies have reported that in nerves subjected to IR, there are releases of inflammatory mediators such as inducible nitric oxide synthase, intercellular adhesion molecule-1, tumour necrosis factor-α (TNF-α) and NF-κB. 24,25 This concept has been confirmed by our previous study which demonstrated that VPN induced by IR in the rat femoral artery activates the transcription factor NF-κB as well as the pro-inflammatory cytokines TNF-α and interleukin-1β (IL-1β) in the sciatic nerve. 9 TNF-α has been reported to be upregulated in animal models of nerve injury and participates in the generation of neuropathic pain, 1,28,29 while IL-1β has been known to directly sensitize nociceptors.…”

DL-2-amino-3-phosphonopropionic acid protects primary neurons from oxygen-glucose deprivation induced injury

“…An in vitro study indicated that glutamate receptors antagonists have neuroprotective abilities in primary cultures of rat cerebellar granule cells, briefly exposed to glutamate [12]. Ke et al have found that MK-801 may alleviate ischemia/reperfusion injury of rat sciatic nerve by inhibiting the activation of tumor necrosis factor-α [13]. Adachi et al found that phencyclidine-induced the decrease of synaptic connectivity by inhibiting the secretion of brain-derived neurotrophic factor in cultured cortical neurons [14].…”