MyMedR

Displaying all 6 publications

Abstract:

Sort:

Fulltext TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia

Poore CP, Hazalin NAMN, Wei S, Low SW, Chen B, Nilius B, et al.

Neurobiol Dis, 2024 Feb;191:106408.
PMID: 38199274 DOI: 10.1016/j.nbd.2024.106408

Excitotoxicity arises from unusually excessive activation of excitatory amino acid receptors such as glutamate receptors. Following an energy crisis, excitotoxicity is a major cause for neuronal death in neurological disorders. Many glutamate antagonists have been examined for their efficacy in mitigating excitotoxicity, but failed to generate beneficial outcome due to their side effects on healthy neurons where glutamate receptors are also blocked. In this study, we found that during chronic hypoxia there is upregulation and activation of a nonselective cation channel TRPM4 that contributes to the depolarized neuronal membrane potential and enhanced glutamate-induced calcium entry. TRPM4 is involved in modulating neuronal membrane excitability and calcium signaling, with a complex and multifaceted role in the brain. Here, we inhibited TRPM4 using a newly developed blocking antibody M4P, which could repolarize the resting membrane potential and ameliorate calcium influx upon glutamate stimulation. Importantly, M4P did not affect the functions of healthy neurons as the activity of TRPM4 channel is not upregulated under normoxia. Using a rat model of chronic hypoxia with both common carotid arteries occluded, we found that M4P treatment could reduce apoptosis in the neurons within the hippocampus, attenuate long-term potentiation impairment and improve the functions of learning and memory in this rat model. With specificity to hypoxic neurons, TRPM4 blocking antibody can be a novel way of controlling excitotoxicity with minimal side effects that are common among direct blockers of glutamate receptors.

Matched MeSH terms: Receptors, Glutamate/metabolism
Fulltext Cerebral protection: a review of current techniques

Palur, Ravikant

Medical Health Reviews, 2009;2009(1):15-42.
MyJurnal

The brain is considered the most eloquent organ in the human body as its activities impacts on all other systems. Though protected physically (in a bony covering), physiologically through the blood-CSF barrier (from invading organisms and toxins) and hemodynamically through the phenomenon of cerebral autoregulation; the brain is open to insults of various kinds which can critically damage this structure. Intracellular Ca++ accumulation, excessive activation of excitatory amino acid receptors, lipid peroxidation and free radical releaserelated damage are but a few of the pathological processes that occur at the neuronal level leading to damage. The mechanism by which the brain can be provided protection when it is in a compromised state or likely to be compromised is known as cerebral protection. There are various modalities of pharmacologic (use of barbiturates, etomidate, isoflurane, steroids, Ca++, corticosteroids etc) and non-pharmacologic therapies (hypothermia, hyperventilation, induced hypotension, electrophysiologic monitoring, endovascular management etc) available for cerebral protection which finds place in the armamentarium of clinicians managing the critically injured brain. Our knowledge of the functioning of the brain at the molecular level and the various biochemico-pathological processes that are set into motion during critical states continues to evolve. This review article attempts to explain present understanding of the biochemical and pathological processes involved in neuronal damage while also looking at current available therapies (pharmacologic & nonpharmacologic) being utilized in different clinical settings.

Matched MeSH terms: Receptors, Glutamate
Fulltext Alcohol Use Disorder, Neurodegeneration, Alzheimer's and Parkinson's Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Kamal H, Tan GC, Ibrahim SF, Shaikh MF, Mohamed IN, Mohamed RMP, et al.

Front Cell Neurosci, 2020;14:282.
PMID: 33061892 DOI: 10.3389/fncel.2020.00282

Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer's and Parkinson's disease.

Matched MeSH terms: Receptors, Glutamate
Fulltext Evaluation and Comparison of Trachyspermum ammi Seed Extract for Its Anti-inflammatory Effect

Aslam A, Nokhala A, Peerzada S, Ahmed S, Khan T, Siddiqui MJ

J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S777-S780.
PMID: 33828377 DOI: 10.4103/jpbs.JPBS_243_19

Aims and Objectives: The present study was aimed to evaluate the antiinflammatory effect of different seed extracts of Trachyspermum ammi at different doses.
Materials and Methods: Three different seed extracts were prepared through Soxhlet extraction method by using n-hexane, chloroform and methanol solvents. Acute toxicity test performed at dose of 400 mg/ kg, 800 mg/kg, 1600 mg/kg and 3200 mg/kg. Two different strengths of seed extracts (minimum therapeutic dose of 500 mg/kg and maximum therapeutic dose of 1000 mg/kg) were given to Wistar rats to measure anti-inflammatory activity through Carrageenan induced paw edema method.
Results: The standard drug diclofenac sodium was (percentage of inhibition of paw edema 29.68%) more effective as compared to test drug. When efficacy of all extracts compared with each other, n-hexane extract showed more anti-inflammatory effect (percentage inhibition of paw edema 22.21%) at maximum effective dose 1000 mg/kg.
Conclusion: Seed extracts of T. ammi showed anti-inflammatory activity by potentiating the neurotransmission of GABA and also by repression glutamate receptor.

Matched MeSH terms: Receptors, Glutamate
Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors

Ayoub R, Jarrar Q, Ali D, Moshawih S, Jarrar Y, Hakim M, et al.

Eur J Pharm Sci, 2021 Aug 01;163:105865.
PMID: 33979659 DOI: 10.1016/j.ejps.2021.105865

BACKGROUND: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy.
METHOD: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations.
RESULTS: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA.
CONCLUSION: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.

Matched MeSH terms: Receptors, Glutamate
Glutamate receptors and transporters as comparative cues to the glutamatergic circuits of the avian and mammalian brain

Islam, M.R., Muzaimi, M., Abdullah, J.M.

Orient Neuron Nexus, 2011;2(1):2-9.
MyJurnal

Glutamate is the principal excitatory neurotransmitter in the central nervous system, and plays important roles in both physiological and pathological neuronal processes. Current understanding of the exact mechanisms involved in glutamate-induced neuronal excitotoxicity, in which excessive glutamate causes neuronal dysfunction and degeneration, whether acute or chronic, remain elusive. Conditions, due to acute insults such as ischaemia and traumatic brain injury, and chronic neurodegenerative disorders such as multiple sclerosis and motor neuron disease, suffer from the lack of translational neuroprotection in clinical setting to tackle glutamate excitotoxicity despite steady growth of animal studies that revealed complex cell death pathway interactions. In addition, glutamates are also released by non-neuronal cells including astrocytes and oligodendroglia. Thus, attempts to elucidate this complexity are closely related to our understanding of the glutamatergic circuitry in the brain. Neuronal cells develop a glutamatergic system at glutamatergic synapses that utilise glutamate as an intercellular signaling molecule to characterise the output, input, and termination of this signaling. As to signal input, various kinds of glutamate receptors have been identified and characterized. Na+-dependent glutamate transporters at the plasma membrane are responsible for the signal termination through sequestration of glutamate from the synaptic cleft. The signal output systems comprise vesicular storage and subsequent exocytosis of glutamate by using vesicular glutamate transporters. Similar to the mammalian brain, the regional differences of glutamatergic neurons and glutamate receptor neurons suggest many glutamatergic projections in the avian brain, as supported by recent evidence of glutamate-related genes distribution. Glutamatergic target areas are expected to show high activity of glutamate transporters that remove released glutamate from the synaptic clefts. This review summarises and compares glutamatergic circuits in the avian and mammalian brain, particularly in the olfactory pathway, the paffial organization of glutamatergic neurons and connection with the striatum, hippocampal-septal pathway, visual and auditory pathways, and granule cell-Purkinje cell pathway in the cerebellum. Comparative appreciation of these glutamatergic circuits, particularly with the localisation and/or expression of specific subtypes of glutamate transporters, would provide the morphological basis for physiological and pharmacological designs that supplement existing animal studies of the current proposed mechanisms that underlie glutamate-induced neuronal excitotoxicity.

Matched MeSH terms: Receptors, Glutamate