Displaying all 18 publications

  1. 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
  2. Lee, CL, Zainuddin AA, Abdul Karim AK, Yulianty A, Law, ZK, Md.Isa N, et al.
    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
  3. 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
  4. Noh ASM, Ismail CAN
    Malays J Med Sci, 2020 Feb;27(1):6-21.
    PMID: 32158341 MyJurnal DOI: 10.21315/mjms2020.27.1.2
    Chronic pain is a debilitating condition that occurs after tissue damage, which substantially affects the patient's emotional state and physical activity. The chronic pain in rheumatoid arthritis (RA) is the result of various autoimmune-induced inflammatory reactions in the joints. Both types of peripheral and central pain processing can lead to sensitisation. Non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) can result in potent anti-inflammatory effect. However, these drugs are not able to suppress the pain from RA for a prolonged period. For years, researchers have examined the role of the N-methyl-D-aspartic acid receptor 2B (NR2B) subunit of N-methyl-D-aspartate receptors (NMDAR) in chronic and neuropathic pain models. This NMDAR subtype can be found in at the peripheral and central nervous system and it represents an effective therapy for RA pain management. This review focuses on the NR2B subunit of NMDAR and the different pathways leading to its activation. Furthermore, specific attention is given to the possible involvement of NR2B subunit in the peripheral and central pathogenesis of RA.
    Matched MeSH terms: N-Methylaspartate
  5. Iezhitsa I, Agarwal R
    Neural Regen Res, 2021 May;16(5):967-971.
    PMID: 33229737 DOI: 10.4103/1673-5374.297059
    Glaucoma is a range of progressive optic neuropathies characterized by progressive retinal ganglion cell loss and visual field defects. It is recognized as a leading cause of irreversible blindness affecting more than 70 million people worldwide. Currently, reduction of intraocular pressure, a widely recognized risk factor for glaucoma development, is the only pharmacological strategy for slowing down retinal ganglion cell loss and disease progression. However, retinal ganglion cell death and visual field loss have been observed in normotensive glaucoma, suggesting that the disease process is partially independent of intraocular pressure. Taurine is one of the agents that have attracted attention of researchers recently. Taurine has been shown to be involved in multiple cellular functions, including a central role as a neurotransmitter, as a trophic factor in the central nervous system development, as an osmolyte, as a neuromodulator, and as a neuroprotectant. It also plays a role in the maintenance of the structural integrity of the membranes and in the regulation of calcium transport and homeostasis. Taurine is known to prevent N-methyl-D-aspartic acid-induced excitotoxic injury to retinal ganglion cells. A recently published study clearly demonstrated that taurine prevents retinal neuronal apoptosis both in vivo and in vitro. Protective effect of taurine may be attributed to direct inhibition of apoptosis, an activation of brain derived neurotrophic factor-related neuroprotective mechanisms and reduction of retinal oxidative and nitrosative stresses. Further studies are needed to fully explore the potential of taurine as a neuroprotective agent, so that it can be applied in clinical practice, particularly for the treatment of glaucoma. The objective of current review was to summarize recent evidence on neuroprotective properties of taurine in glaucoma.
    Matched MeSH terms: N-Methylaspartate
  6. 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
  7. 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*
  8. 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
  9. 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*
  10. 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*
  11. 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
  12. 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
  13. Bansal Y, Singh R, Parhar I, Kuhad A, Soga T
    Front Pharmacol, 2019;10:452.
    PMID: 31164818 DOI: 10.3389/fphar.2019.00452
    Depression is an incapacitating neuropsychiatric disorder. The serotonergic system in the brain plays an important role in the pathophysiology of depression. However, due to delayed and/or poor performance of selective serotonin reuptake inhibitors in treating depressive symptoms, the role of the serotonergic system in depression has been recently questioned further. Evidence from recent studies suggests that increased inflammation and oxidative stress may play significant roles in the pathophysiology of depression. The consequences of these factors can lead to the neuroprogression of depression, involving neurodegeneration, astrocytic apoptosis, reduced neurogenesis, reduced plasticity (neuronal and synaptic), and enhanced immunoreactivity. Specifically, increased proinflammatory cytokine levels have been shown to activate the kynurenine pathway, which causes increased production of quinolinic acid (QA, an N-Methyl-D-aspartate agonist) and decreases the synthesis of serotonin. QA exerts many deleterious effects on the brain via mechanisms including N-methyl-D-aspartate excitotoxicity, increased oxidative stress, astrocyte degeneration, and neuronal apoptosis. QA may also act directly as a pro-oxidant. Additionally, the nuclear translocation of antioxidant defense factors, such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is downregulated in depression. Hence, in the present review, we discuss the role of QA in increasing oxidative stress in depression by modulating the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and thus affecting the synthesis of antioxidant enzymes.
    Matched MeSH terms: N-Methylaspartate
  14. 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
  15. 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
  16. Ismail CAN, Suppian R, Ab Aziz CB, Long I
    J Mol Neurosci, 2021 Feb;71(2):379-393.
    PMID: 32671697 DOI: 10.1007/s12031-020-01661-1
    The pharmacological inhibition of glial activation is one of the new approaches for combating neuropathic pain in which the role of glia in the modulation of neuropathic pain has attracted significant interest and attention. Neuron-glial crosstalk is achieved with N-methyl-D-aspartate-2B receptor (NMDAR-2B) activation. This study aims to determine the effect of ifenprodil, a potent noncompetitive NMDAR-2B antagonist, on activated microglia, brain-derived neurotrophic factors (BDNF) and downstream regulatory element antagonist modulator (DREAM) protein expression in the spinal cord of streptozotocin-induced painful diabetic neuropathy (PDN) rats following formalin injection. In this experimentation, 48 Sprague-Dawley male rats were randomly selected and divided into four groups: (n = 12): control, PDN, and ifenprodil-treated PDN rats at 0.5 μg or 1.0 μg for 7 days. Type I diabetes mellitus was then induced by injecting streptozotocin (60 mg/kg, i.p.) into the rats which were then over a 2-week period allowed to progress into the early phase of PDN. Ifenprodil was administered in PDN rats while saline was administered intrathecally in the control group. A formalin test was conducted during the fourth week to induce inflammatory nerve injury, in which the rats were sacrificed at 72 h post-formalin injection. The lumbar enlargement region (L4-L5) of the spinal cord was dissected for immunohistochemistry and western blot analyses. The results demonstrated a significant increase in formalin-induced flinching and licking behavior with an increased spinal expression of activated microglia, BDNF and DREAM proteins. It was also shown that the ifenprodil-treated rats following both doses reduced the extent of their flinching and duration of licking in PDN in a dose-dependent manner. As such, ifenprodil successfully demonstrated inhibition against microglia activation and suppressed the expression of BDNF and DREAM proteins in the spinal cord of PDN rats. In conclusion, ifenprodil may alleviate PDN by suppressing spinal microglia activation, BDNF and DREAM proteins.
    Matched MeSH terms: N-Methylaspartate
  17. Aye SZ, Ni H, Sein HH, Mon ST, Zheng Q, Wong YKY
    Cochrane Database Syst Rev, 2021 Feb 14;2:CD013457.
    PMID: 33583058 DOI: 10.1002/14651858.CD013457.pub2
    BACKGROUND: Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted.

    OBJECTIVES: To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD.

    SEARCH METHODS: In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events.  SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD.

    DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review.

    MAIN RESULTS: We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted at two sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out 1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment. The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reported low certainty evidence of little to no difference between the two groups for all outcomes measured at one week post-treatment: social interaction impairment (mean difference (MD) 3.61 (assessed with the Social Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment (MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD (RR 0.97 (measured by the Clinical Global Impression-Improvement scale), 95% CI 0.49 to 1.93); and tolerability of D-cycloserine (RR 0.32 (assessed by the number of dropouts), 95% CI 0.01 to 7.68).  AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.

    Matched MeSH terms: N-Methylaspartate
  18. 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*
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