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  1. Chia JSM, Izham NAM, Farouk AAO, Sulaiman MR, Mustafa S, Hutchinson MR, et al.
    Front Pharmacol, 2020;11:92.
    PMID: 32194397 DOI: 10.3389/fphar.2020.00092
    Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone's anti-neuropathic effects. The present study was conducted to determine zerumbone's modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists- prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration.
    Matched MeSH terms: N-Methylaspartate
  2. Abd Jalil A, Khaza'ai H, Nordin N, Mansor N, Zaulkffali AS
    PMID: 29348770 DOI: 10.1155/2017/6048936
    Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate in the brain can be excitotoxic and cause oxidative stress, which is associated with Alzheimer's disease. In the present study, the effects of vitamin E in the form of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP) in modulating the glutamate receptor and neuron injury markers in an in vitro model of oxidative stress in neural-derived embryonic stem (ES) cell cultures were elucidated. A transgenic mouse ES cell line (46C) was differentiated into a neural lineage in vitro via induction with retinoic acid. These cells were then subjected to oxidative stress with a significantly high concentration of glutamate. Measurement of reactive oxygen species (ROS) was performed after inducing glutamate excitotoxicity, and recovery from this toxicity in response to vitamin E was determined. The gene expression levels of glutamate receptors and neuron-specific enolase were elucidated using real-time PCR. The results reveal that neural cells derived from 46C cells and subjected to oxidative stress exhibit downregulation of NMDA, kainate receptor, and NSE after posttreatment with different concentrations of TRF and α-TCP, a sign of neurorecovery. Treatment of either TRF or α-TCP reduced the levels of ROS in neural cells subjected to glutamate-induced oxidative stress; these results indicated that vitamin E is a potent antioxidant.
    Matched MeSH terms: N-Methylaspartate
  3. Abd Aziz CB, Hasim H, Zakaria R, Ahmad AH
    Turk J Pharm Sci, 2020 Dec 23;17(6):620-625.
    PMID: 33389951 DOI: 10.4274/tjps.galenos.2019.21548
    Objectives: This study investigated whether the alterations in memory and hippocampus morphology and levels of malondialdehyde (MDA) and N-methyl-D-aspartate (NMDA) receptor in the hippocampus of adult rats after prenatal stress could be prevented by administration of Tualang honey (TH).

    Materials and Methods: Twenty-four pregnant rats were randomly grouped into a control group (C), a stress group (S), and a stress group treated with TH. Eight male pups from each group were randomly chosen and they were sacrificed at eight or ten weeks of age following the novel object recognition test. Their brains were removed and histological changes and levels of MDA and NMDA receptors in the hippocampus were determined.

    Results: The offspring from TH group showed significantly increased preference index (p<0.05) with higher neuronal number compared to S group. A significantly lower level of MDA and NMDA receptors were shown in TH group (P<0.01; P<0.05 respectively) compared to S group. The parameters investigated were not significantly different between C and TH groups.

    Conclusion: The study has shown that memory alteration, changes in hippocampus histology, MDA and NMDA receptor levels could be prevented by TH administration during prenatal stress. The results suggest the beneficial effects of Tualang honey in prenatally stressed rat offspring.

    Matched MeSH terms: N-Methylaspartate
  4. Jafri AJA, Agarwal R, Iezhitsa I, Agarwal P, Ismail NM
    Amino Acids, 2019 Apr;51(4):641-646.
    PMID: 30656415 DOI: 10.1007/s00726-019-02696-4
    This study aimed to evaluate effect of TAU on NMDA-induced changes in retinal redox status, retinal cell apoptosis and retinal morphology in Sprague-Dawley rats. Taurine was injected intravitreally as pre-, co- or post-treatment with NMDA and 7 days post-treatment retinae were processed for estimation of oxidative stress, retinal morphology using H&E staining and retinal cell apoptosis using TUNEL staining. Treatment with TAU, particularly pre-treatment, significantly increased retinal glutathione, superoxide dismutase and catalase levels compared to NMDA-treated rats; whereas, the levels of malondialdehyde reduced significantly. Reduction in retinal oxidative stress in TAU pre-treated group was associated with significantly greater fractional thickness of ganglion cell layer within inner retina and retinal cell density in inner retina. TUNEL staining showed significantly reduced apoptotic cell count in TAU pre-treated group compared to NMDA group. It could be concluded that TAU protects against NMDA-induced retinal injury in rats by reducing retinal oxidative stress.
    Matched MeSH terms: N-Methylaspartate/toxicity*
  5. Kalinichenko LS, Smaga I, Filip M, Lenz B, Kornhuber J, Müller CP
    Behav Brain Res, 2023 Feb 15;439:114225.
    PMID: 36435218 DOI: 10.1016/j.bbr.2022.114225
    Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the "developmental programming" of long-term consequences of prenatal stress in foetuses of both sexes. We observed that severe prenatal stress in the model of repeated corticosterone injections enhanced brain levels of corticosterone and testosterone in male foetuses. The expression of GluN1 and GluN2A, but not GluN2B NMDA receptor subunits were significantly reduced in the brain of stressed male foetuses. However, female foetuses were protected against stress effects on the brain corticosterone and testosterone levels. More moderate types of stress, such as repeated restraint stress and chronic unpredictable stress, did not induce an increase in brain corticosterone in dams and testosterone concentrations in foetuses of both sexes. Moreover, chronic unpredictable stress reduced brain testosterone concentration in male foetuses. Altogether, changes in brain testosterone level might be one of the crucial mechanisms determining the development of long-term consequences of severe prenatal stress in male, but not in female foetuses. Targeting this mechanism might allow to develop principally new prediction and therapeutic approaches for prenatal stress-associated psychiatric disorders.
    Matched MeSH terms: N-Methylaspartate/metabolism
  6. Kaka U, Saifullah B, Abubakar AA, Goh YM, Fakurazi S, Kaka A, et al.
    BMC Vet Res, 2016 Sep 9;12(1):198.
    PMID: 27612660
    Central sensitization is a potential severe consequence of invasive surgical procedures. It results in postoperative and potentially chronic pain enhancement. It results in postoperative pain enhancement; clinically manifested as hyperalgesia and allodynia. N-methyl-D-aspartate (NMDA) receptor plays a crucial role in the mechanism of central sensitisation. Ketamine is most commonly used NMDA-antagonist in human and veterinary practice. However, the antinociceptive serum concentration of ketamine is not yet properly established in dogs. Six dogs were used in a crossover design, with one week washout period. Treatments consisted of: 1) 0.5 mg/kg ketamine followed by continuous rate infusion (CRI) of 30 μg/kg/min; 2) 0.5 mg/kg ketamine followed by CRI of 30 μg/kg/min and lidocaine (2 mg/kg followed by CRI of 100 μg/kg/min); and 3) 0.5 mg/kg ketamine followed by CRI of 50 μg/kg/min. The infusion was administered up to 120 min. Nociceptive thresholds and ketamine serum concentrations were measured before drug administration, and at 5, 10, 20, 40, 60, 90, 120, 140 and 160 min after the start of infusion.
    Matched MeSH terms: N-Methylaspartate
  7. Lah MHC, Reza F, Begum T, Abdullah JM
    Malays J Med Sci, 2018 May;25(3):27-39.
    PMID: 30899185 MyJurnal DOI: 10.21315/mjms2018.25.3.4
    Background: Previous studies from animal models have shown that pre-synaptic NMDA receptors (preNMDARs) are present in the cortex, but the role of inhibition mediated by preNMDARs during epileptogenesis remains unclear. In this study, we wanted to observe the changes in GABAergic inhibition through preNMDARs in sensory-motor and visual cortical pyramidal neurons after pilocarpine-induced status epilepticus.

    Methods: Using a pilocarpine-induced epileptic mouse model, sensory-motor and visual cortical slices were prepared, and the whole-cell patch clamp technique was used to record spontaneous inhibitory post-synaptic currents (sIPSCs).

    Results: The primary finding was that the mean amplitude of sIPSC from the sensory-motor cortex increased significantly in epileptic mice when the recording pipette contained MK-801 compared to control mice, whereas the mean sIPSC frequency was not significantly different, indicating that post-synaptic mechanisms are involved. However, there was no significant pre-synaptic inhibition through preNMDARs in the acute brain slices from pilocarpine-induced epileptic mice.

    Conclusion: In the acute case of epilepsy, a compensatory mechanism of post-synaptic inhibition, possibly from ambient GABA, was observed through changes in the amplitude without significant changes in the frequency of sIPSC compared to control mice. The role of preNMDAR-mediated inhibition in epileptogenesis during the chronic condition or in the juvenile stage warrants further investigation.

    Matched MeSH terms: N-Methylaspartate
  8. Jafri AJA, Agarwal R, Iezhitsa I, Agarwal P, Spasov A, Ozerov A, et al.
    Mol Vis, 2018;24:495-508.
    PMID: 30090013
    Purpose: Retinal nitrosative stress associated with altered expression of nitric oxide synthases (NOS) plays an important role in excitotoxic retinal ganglion cell loss in glaucoma. The present study evaluated the effects of magnesium acetyltaurate (MgAT) on changes induced by N-methyl-D-aspartate (NMDA) in the retinal expression of three NOS isoforms, retinal 3-nitrotyrosine (3-NT) levels, and the extent of retinal cell apoptosis in rats. Effects of MgAT with taurine (TAU) alone were compared to understand the benefits of a combined salt of Mg and TAU.

    Methods: Excitotoxic retinal injury was induced with intravitreal injection of NMDA in Sprague-Dawley rats. All treatments were given as pre-, co-, and post-treatment with NMDA. Seven days post-injection, the retinas were processed for measurement of the expression of NOS isoforms using immunostaining and enzyme-linked immunosorbent assay (ELISA), retinal 3-NT content using ELISA, retinal histopathological changes using hematoxylin and eosin (H&E) staining, and retinal cell apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining.

    Results: As observed on immunohistochemistry, the treatment with NMDA caused a 4.53-fold increase in retinal nNOS expression compared to the PBS-treated rats (p<0.001). Among the MgAT-treated groups, only the pretreatment group showed significantly lower nNOS expression than the NMDA-treated group with a 2.00-fold reduction (p<0.001). Among the TAU-treated groups, the pre- and cotreatment groups showed 1.84- and 1.71-fold reduction in nNOS expression compared to the NMDA-treated group (p<0.001), respectively, but remained higher compared to the PBS-treated group (p<0.01). Similarly, iNOS expression in the NMDA-treated group was significantly greater than that for the PBS-treated group (2.68-fold; p<0.001). All MgAT treatment groups showed significantly lower iNOS expression than the NMDA-treated groups (3.58-, 1.51-, and 1.65-folds, respectively). However, in the MgAT co- and post-treatment groups, iNOS expression was significantly greater than in the PBS-treated group (1.77- and 1.62-folds, respectively). Pretreatment with MgAT caused 1.77-fold lower iNOS expression compared to pretreatment with TAU (p<0.05). In contrast, eNOS expression was 1.63-fold higher in the PBS-treated group than in the NMDA-treated group (p<0.001). Among all treatment groups, only pretreatment with MgAT caused restoration of retinal eNOS expression with a 1.39-fold difference from the NMDA-treated group (p<0.05). eNOS expression in the MgAT pretreatment group was also 1.34-fold higher than in the TAU pretreatment group (p<0.05). The retinal NOS expression as measured with ELISA was in accordance with that estimated with immunohistochemistry. Accordingly, among the MgAT treatment groups, only the pretreated group showed 1.47-fold lower retinal 3-NT than the NMDA-treated group, and the difference was significant (p<0.001). The H&E-stained retinal sections in all treatment groups showed statistically significantly greater numbers of retinal cell nuclei than the NMDA-treated group in the inner retina. However, the ganglion cell layer thickness in the TAU pretreatment group remained 1.23-fold lower than that in the MgAT pretreatment group (p<0.05). In line with this observation, the number of apoptotic cells as observed after TUNEL staining was 1.69-fold higher after pretreatment with TAU compared to pretreatment with MgAT (p<0.01).

    Conclusions: MgAT and TAU, particularly with pretreatment, reduce retinal cell apoptosis by reducing retinal nitrosative stress. Pretreatment with MgAT caused greater improvement in NMDA-induced changes in iNOS and eNOS expression and retinal 3-NT levels than pretreatment with TAU. The greater reduction in retinal nitrosative stress after pretreatment with MgAT was associated with lower retinal cell apoptosis and greater preservation of the ganglion cell layer thickness compared to pretreatment with TAU.

    Matched MeSH terms: N-Methylaspartate/adverse effects; N-Methylaspartate/antagonists & inhibitors*
  9. Jafri AJA, Arfuzir NNN, Lambuk L, Iezhitsa I, Agarwal R, Agarwal P, et al.
    J Trace Elem Med Biol, 2017 Jan;39:147-154.
    PMID: 27908408 DOI: 10.1016/j.jtemb.2016.09.005
    Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL(-1)). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL(-1)) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.
    Matched MeSH terms: N-Methylaspartate/antagonists & inhibitors*; N-Methylaspartate/toxicity
  10. Pui Ping C, Akhtar MN, Israf DA, Perimal EK, Sulaiman MR
    Molecules, 2020 Nov 18;25(22).
    PMID: 33217904 DOI: 10.3390/molecules25225385
    The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in thermal and mechanical pain models; however, the precise mechanism has yet to be examined. The present study investigated the possible mechanisms involved in the antinociceptive activity of cardamonin on protein kinase C, N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors, l-arginine/cyclic guanosine monophosphate (cGMP) mechanism, as well as the ATP-sensitive potassium (K+) channel. Cardamonin was administered to the animals intra-peritoneally. Present findings showed that cardamonin significantly inhibited pain elicited by intraplantar injection of phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator) with calculated mean ED50 of 2.0 mg/kg (0.9-4.5 mg/kg). The study presented that pre-treatment with MK-801 (NMDA receptor antagonist) and NBQX (non-NMDA receptor antagonist) significantly modulates the antinociceptive activity of cardamonin at 3 mg/kg when tested with glutamate-induced paw licking test. Pre-treatment with l-arginine (a nitric oxide precursor), ODQ (selective inhibitor of soluble guanylyl cyclase) and glibenclamide (ATP-sensitive K+ channel inhibitor) significantly enhanced the antinociception produced by cardamonin. In conclusion, the present findings showed that the antinociceptive activity of cardamonin might involve the modulation of PKC activity, NMDA and non-NMDA glutamate receptors, l-arginine/nitric oxide/cGMP pathway and ATP-sensitive K+ channel.
    Matched MeSH terms: N-Methylaspartate
  11. Fazel MF, Abu IF, Mohamad MHN, Agarwal R, Iezhitsa I, Bakar NS, et al.
    PLoS One, 2020;15(7):e0236450.
    PMID: 32706792 DOI: 10.1371/journal.pone.0236450
    Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 μm length and 100 μm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.
    Matched MeSH terms: N-Methylaspartate/toxicity
  12. Lambuk L, Jafri AJ, Arfuzir NN, Iezhitsa I, Agarwal R, Rozali KN, et al.
    Neurotox Res, 2017 01;31(1):31-45.
    PMID: 27568334 DOI: 10.1007/s12640-016-9658-9
    Glutamate excitotoxicity plays a major role in the loss of retinal ganglion cells (RGCs) in glaucoma. The toxic effects of glutamate on RGCs are mediated by the overstimulation of N-methyl-D-aspartate (NMDA) receptors. Accordingly, NMDA receptor antagonists have been suggested to inhibit excitotoxicity in RGCs and delay the progression and visual loss in glaucoma patients. The purpose of the present study was to examine the potential neuroprotective effect of Mg acetyltaurate (MgAT) on RGC death induced by NMDA. MgAT was proposed mainly due to the combination of magnesium (Mg) and taurine which may provide neuroprotection by dual mechanisms of action, i.e., inhibition of NMDA receptors and antioxidant effects. Rats were divided into 5 groups and were given intravitreal injections. Group 1 (PBS group) was injected with vehicle; group 2 (NMDA group) was injected with NMDA while groups 3 (pre-), 4 (co-), and 5 (post-) treatments were injected with MgAT, 24 h before, in combination or 24 h after NMDA injection respectively. NMDA and MgAT were injected in PBS at doses 160 and 320 nmol, respectively. Seven days after intravitreal injection, the histological changes in the retina were evaluated using hematoxylin & eosin (H&E) staining. Optic nerves were dissected and stained in Toluidine blue for grading on morphological neurodegenerative changes. The extent of apoptosis in retinal tissue was assessed by TUNEL assay and caspase-3 immunohistochemistry staining. The estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors and caspase-3 activity in retina was done using enzyme-linked immunosorbent assay (ELISA) technique. The retinal morphometry showed reduced thickness of ganglion cell layer (GCL) and reduction in the number of retinal cells in GCL in NMDA group compared to the MgAT-treated groups. TUNEL and caspase-3 staining showed increased number of apoptotic cells in inner retina. The results were further corroborated by the estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors, and caspase-3 activity in retina. In conclusion, current study revealed that intravitreal MgAT prevents retinal and optic nerve damage induced by NMDA. Overall, our data demonstrated that the pretreatment with MgAT was more effective than co- and posttreatment. This protective effect of MgAT against NMDA-induced retinal cell apoptosis could be attributed to the reduction of retinal oxidative stress and activation of BDNF-related neuroprotective mechanisms.
    Matched MeSH terms: N-Methylaspartate/toxicity*
  13. Hsu CK, Chang SJ, Lim LY, Chang HH, Shei-Dei Yang S
    J Vasc Res, 2023;60(3):137-147.
    PMID: 37285812 DOI: 10.1159/000529916
    N-methyl-D-aspartate (NMDA) receptors were found to be dysfunctional in hypertensive rats. Methyl palmitate (MP) has been shown to diminish the nicotine-induced increase in blood flow in the brainstem. The aim of this study was to determine how MP modulated NMDA-induced increased regional cerebral blood flow (rCBF) in normotensive (WKY), spontaneously hypertensive (SHR), and renovascular hypertensive (RHR) rats. The increase in rCBF after the topical application of experimental drugs was measured using laser Doppler flowmetry. Topical NMDA application induced an MK-801-sensitive increase in rCBF in anesthetized WKY rats, which was inhibited by MP pretreatments. This inhibition was prevented by pretreatment with chelerythrine (a PKC inhibitor). The NMDA-induced increase in rCBF was also inhibited by the PKC activator in a concentration-dependent manner. Neither MP nor MK-801 affected the increase in rCBF induced by the topical application of acetylcholine or sodium nitroprusside. Topical application of MP to the parietal cortex of SHRs, on the other hand, increased basal rCBF slightly but significantly. MP enhanced the NMDA-induced increase in rCBF in SHRs and RHRs. These results suggested that MP had a dual effect on the modulation of rCBF. MP appears to play a significant physiological role in CBF regulation.
    Matched MeSH terms: N-Methylaspartate/toxicity
  14. Hidani Hasim, Che Badariah Abd Aziz, Siti Qusyasyiah Ahmad Suhaimi, Mahaneem Mohamed, Idris Long, Rahimah Zakaria
    MyJurnal
    Introduction: Increased nociceptive responses were shown in the offspring of prenatally stressed rats. Reports have demonstrated the anti-nociceptive effects of Tualang honey in the rat offspring. The present study was done to de- termine whether the modulation of nociceptive behaviour by Tualang honey was mediated by modulating changes in the histology, oxidative stress parameters and N-methyl-D-aspartate (NMDA) receptors in the thalamus of the rat offspring. Methods: Eighteen Sprague Dawley pregnant rats were randomly assigned to control (C), stress (S) and stress-treated with Tualang honey (SH) groups. Stress was given in a form of restraint stress.Tualang honey was given to SH group from first day of pregnancy until delivery. Thirty-three adult male offspring were subjected to formalin test before they were sacrificed. Nociceptive behaviour score, number of neurons, level of oxidative stress parameters and NMDA receptors in the thalamus were analysed by using one-way ANOVA. Results: The study demonstrated a significant decrease in mean nociceptive behaviour score (p
    Matched MeSH terms: N-Methylaspartate
  15. Lambuk L, Iezhitsa I, Agarwal R, Bakar NS, Agarwal P, Ismail NM
    Neurotoxicology, 2019 01;70:62-71.
    PMID: 30385388 DOI: 10.1016/j.neuro.2018.10.009
    OBJECTIVE: N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure.

    METHODOLOGY: Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with PBS and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure respectively. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique.

    RESULTS: Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 μm length (by 1.5-fold, p 

    Matched MeSH terms: N-Methylaspartate/toxicity*
  16. Lee, CL, Zainuddin AA, Abdul Karim AK, Yulianty A, Law, ZK, Md.Isa N, et al.
    MyJurnal
    We report a rare case of altered mental status in a young patient with immature ovarian teratoma. A 22-year-old woman presented with seizures, hallucination, amnesia and orofacial dyskinesia. Examination and investigation revealed an ovarian massand asalphing-oophorectomy was performed. The histopathological examination result showed an immature teratoma grade 2 with thepresence of immature primitive glial tissue. Her CSF N-Methyl-D-Aspartic acid receptor (Anti-NMDAR) antibodytest was positive. N-Methyl-D-Aspartic acid receptor antibody associated limbic encephalitis is an autoimmune antibody-mediated neuropsychiatric disorder. Resection of the tumour and immunotherapy resulted in full recovery.
    Matched MeSH terms: N-Methylaspartate
  17. Wan Nasru WN, Ab Razak A, Yaacob NM, Wan Azman WN
    Malays J Pathol, 2021 Apr;43(1):25-32.
    PMID: 33903302
    INTRODUCTION: The amino acids that function as co-agonists at the N-methyl-D-aspartate (NMDA) receptor have been investigated in bipolar disorder (BD). However, studies comparing amino acid levels in the plasma of BD patients with healthy controls have yielded inconsistent results. We, therefore, conducted a study in Hospital Universiti Sains Malaysia to determine the plasma levels of glutamate, glycine, and alanine in BD patients and compared them with the healthy controls.

    MATERIALS AND METHODS: An overnight fast of 10-hour plasma levels of glutamate, glycine, alanine, and tryptophan were measured in 83 bipolar patients, and were compared to a group of 82 healthy controls.

    RESULTS: The mean (SD) age of bipolar patients was 40.9 (12.1), while the mean (SD) age for control groups was 35.6 (7.7) years. The median (25th, 75th percentile) of glutamate and alanine levels in bipolar patients was 111.0 (65.0,176.0) and 530.0 (446.0,629.0), respectively, while the mean (SD) of glycine level in bipolar patients was 304.0 (98.1). Significant higher glutamate, glycine, and alanine levels were found in bipolar disorder patients in the manic episode as compared to the healthy controls.

    CONCLUSION: Although the exact relationship between peripheral NMDA receptor co-agonist levels in the pathogenesis of BD is not well understood, these findings should be explored and may enlighten some new paths for BD therapy which could reward the patients also clinicians.

    Matched MeSH terms: N-Methylaspartate
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