scholarly journals MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium–Pilocarpine Model of Epilepsy

2022 ◽  
Vol 23 (1) ◽  
pp. 497
Author(s):  
Alexandra V. Dyomina ◽  
Anna A. Kovalenko ◽  
Maria V. Zakharova ◽  
Tatiana Yu. Postnikova ◽  
Alexandra V. Griflyuk ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Neuroprotective Effect ◽  
Neuronal Loss ◽  
Brain Diseases ◽  
Excitatory Amino Acid Transporter ◽  
Wide Range ◽  
Pilocarpine Model ◽  
Mglur5 Antagonist ◽  
Behavioral Impairments

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium–pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.

scholarly journals Anakinra Reduces Epileptogenesis, Provides Neuroprotection, and Attenuates Behavioral Impairments in Rats in the Lithium–Pilocarpine Model of Epilepsy

2020 ◽  
Vol 13 (11) ◽  
pp. 340
Author(s):  
Alexandra V. Dyomina ◽  
Olga E. Zubareva ◽  
Ilya V. Smolensky ◽  
Dmitry S. Vasilev ◽  
Maria V. Zakharova ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Excitatory Amino Acid ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Chronic Phase ◽  
Marker Genes ◽  
Excitatory Amino Acid Transporter ◽  
Pilocarpine Model ◽  
Behavioral Impairments

Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.

scholarly journals Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Charles Finsterwald ◽  
Sara Dias ◽  
Pierre J. Magistretti ◽  
Sylvain Lengacher
Keyword(s):  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Brain Diseases ◽  
Mitochondrial Activity ◽  
Ganglioside Gm1 ◽  
Neuroprotective Effects ◽  
Wide Range ◽  
Cord Injury ◽  
Clinical Benefits ◽  
The Brain

Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington’s disease and Parkinson’s disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects.

scholarly journals Ceftriaxone Treatment Affects EAAT2 Expression and Glutamatergic Neurotransmission and Exerts a Weak Anticonvulsant Effect in Young Rats

2019 ◽  
Vol 20 (23) ◽  
pp. 5852 ◽  
Author(s):  
Zaitsev ◽  
Malkin ◽  
Postnikova ◽  
Smolensky ◽  
Zubareva ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Temporal Cortex ◽  
Young Male ◽  
Anticonvulsant Effect ◽  
Maximal Electroshock ◽  
Glutamatergic Neurotransmission ◽  
Excitatory Amino Acid Transporter ◽  
Young Rats ◽  
Wide Range

Epilepsy is a common neurological disorder. Despite the availability of a wide range of antiepileptic drugs, these are unsuccessful in preventing seizures in 20–30% of patients. Therefore, new pharmacological strategies are urgently required to control seizures. Modulation of glutamate uptake may have potential in the treatment of pharmacoresistant forms of epilepsy. Previous research showed that the antibiotic ceftriaxone (CTX) increased the expression and functional activity of excitatory amino acid transporter 2 (EAAT2) and exerted considerable anticonvulsant effects. However, other studies did not confirm a significant anticonvulsant effect of CTX administration. We investigated the impacts of CTX treatment on EAAT expression and glutamatergic neurotransmission, as well its anticonvulsant action, in young male Wistar rats. As shown by a quantitative real-time polymerase chain reaction (qPCR) assay and a Western blot analysis, the mRNA but not the protein level of EAAT2 increased in the hippocampus following CTX treatment. Repetitive CTX administration had only a mild anticonvulsant effect on pentylenetetrazol (PTZ)-induced convulsions in a maximal electroshock threshold test (MEST). CTX treatment did not affect the glutamatergic neurotransmission, including synaptic efficacy, short-term facilitation, or the summation of excitatory postsynaptic potentials (EPSPs) in the hippocampus and temporal cortex. However, it decreased the field EPSP (fEPSP) amplitudes evoked by intense electrical stimulation. In conclusion, in young rats, CTX treatment did not induce overexpression of EAAT2, therefore exerting only a weak antiseizure effect. Our data provide new insight into the effects of modulation of EAAT2 expression on brain functioning.

scholarly journals Mechanism of neuroprotective effect of mGluR4 agonists

2019 ◽  
Vol 5 (2) ◽  
pp. 43-47 ◽  
Author(s):  
Natalya V. Avdeeva ◽  
Svetlana A. Sidorova ◽  
Oleg S. Gudyrev ◽  
Ol'ga A. Osipova ◽  
Ivan V. Golubev
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Brain Diseases ◽  
Extracellular Glutamate ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Anti Inflammatory

Introduction: This review of literature is to demonstrate a role of group III metabotropic glutamate receptors in maintaining the level of extracellular glutamate in ischemic stroke and neurodegenerative diseases. Metabotropic glutamate receptors: mGluRs are classified into three groups. It is suggested that the activation of mGluR4 may have a neuroprotective effect. Role of excitotoxicity in the development and severity of various brain diseases: An increase in the concentration of intracellular Ca2+ is the result of excessive accumulation of glutamate in the extracellular space. And a death of nerve cells occurs after a sequence of biochemical reactions, which was called excitotoxicity. It is followed by an imbalance between glutamatergic excitation and GABA-ergic inhibition. As a result of untimely activation of the inhibitory mechanisms, the accumulation of extracellular glutamate, and consequently the death of neurons, continues, which leads to more severe manifestations of the cerebral ischemia. Role of modulation of mGluRs activity in neuroprotection: The literature describes a large number of studies proving that inhibition of hyperactive glutamatergic transmission has a neuroprotective effect. The most likely mechanisms of neuroprotection are inhibition of glutamate production in the substantia nigra, which in turn protects against glutamate-mediated excitotoxicity, and the reduction of the inflammatory effects. Anti-inflammatory effect of mGluR4 agonists in the mechanism of neuroprotective action: The astroglial component may contribute to the protective action of mGluR4 modulators, since astrocytes and microglia have mGluR4. Conclusion: mGluR4 agonists have the neuroprotective and anti-inflammatory effects.

II. Excitatory amino acid receptors in the brain-gut axis

2001 ◽  
Vol 280 (6) ◽  
pp. G1055-G1060 ◽  
Author(s):  
Pamela J. Hornby
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Motor Pattern ◽  
Pattern Generation ◽  
Gut Contents ◽  
Dorsal Vagal Complex ◽  
Gastric Accommodation ◽  
Metabotropic Glutamate ◽  
Therapeutic Benefits ◽  
The Brain

In the last decade, there has been a dramatic increase in academic and pharmaceutical interest in central integration of vago-vagal reflexes controlling the gastrointestinal tract. Associated with this, there have been substantial efforts to determine the receptor-mediated events in the dorsal vagal complex that underlie the physiological responses to distension or variations in the composition of the gut contents. Strong evidence supports the idea that glutamate is a transmitter in afferent vagal fibers conveying information from the gut to the brain, and the implications of this are discussed in this themes article. Furthermore, both ionotropic and metabotropic glutamate receptors mediate pre- and postsynaptic control of glutamate transmission related to several reflexes, including swallowing motor pattern generation, gastric accommodation, and emesis. The emphasis of this themes article is on the potential therapeutic benefits afforded by modulation of these receptors at the site of the dorsal vagal complex.

scholarly journals Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 7822
Author(s):  
Anton N. Shuvaev ◽  
Olga S. Belozor ◽  
Oleg I. Mozhei ◽  
Elena D. Khilazheva ◽  
Andrey N. Shuvaev ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
Average Length ◽  
Glutamate Transporter ◽  
Bergmann Glia ◽  
Spinocerebellar Ataxias ◽  
Excitatory Amino Acid Transporter ◽  
Glial Glutamate Transporter ◽  
Gfap Immunoreactivity ◽  
Cerebellar Ataxias ◽  
Receptor Blockers

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

Question-and-Answer Forum

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S4) ◽  
pp. 13-13
Keyword(s):  
Functional Disability ◽  
Neuroprotective Effect ◽  
Neurodevelopmental Disorder ◽  
Historical Context ◽  
Brain Diseases ◽  
Delayed Treatment ◽  
Disease States ◽  
At Risk Children ◽  
Underlying Mechanisms ◽  
The Impact

AbstractSchizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

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