Expression of mGlu Receptor Genes in the Hippocampus After Intoxication with Trimethyltin

Першина, Е. В.; Mikheeva, I. B.; Kamaltdinova, Elvira; Архипов, В. И.

doi:10.1007/s12031-018-1233-9

Cited by 8 publications

(6 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Damaged mitochondria trigger microglial activation as well as autophagy, most pronounced in the hippocampus one week after TMT intoxication. These cascades remain active in the hippocampus at later time points as well, even after the onetime administration of TMT [12,21]. In the present study, we assessed the morphological and functional state of the hippocampus 3 weeks after TMT injection.…”

Section: Discussionmentioning

confidence: 94%

“…Group III mGluRs in the hippocampus are found predominantly on neuron presynapses. They previously attracted our attention due to the fact that during experimental neurodegeneration induced by trimethyltin chloride (TMT), the level of mGluR4 gene expression in the hippocampus significantly increased 1, 3, and 6 weeks after TMT injection [12]. Given this, we decided to investigate the neuroprotective potential of positive allosteric modulators (PAMs) of Group III mGluRs (which include mGlu7 and mGlu8 as well as mGlu4) when administered together with the non-competitive NMDA receptor antagonist memantine.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

Першина

Chernomorets

Fedorov

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

Першина

Chernomorets

Fedorov

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Minibrain transcriptome showed enrichment for genes that corresponds to various brain regions such as hippocampus, caudate putamen, striatum, sub pallium, nucleus accumbens and cerebral nuclei of the central nervous system (Figure 1 J). TMT is known to severely affect hippocampal neurons specially and thus the enrichment of hippocampal brain region associated genes in minibrain, makes it a suitable model to study TMT induced neurotoxicity (Homayoon et al, 2015; Pershina et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…loss of neuronal function, v. epilepsy and vi. calcium homeostasis dysregulation involved in the neuronal dysfunction associated with TMT neurotoxicity (Supplementary table 4,5, Figure 4C) (Veronesi et al, 1991; Feldman et al, 1993; Halladay et al, 2006; Piacentini et al, 2008; Pershina et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events

Govindan

Alpern

Stoppini

et al. 2022

Preprint

View full text Add to dashboard Cite

Genome-wide transcriptomic interrogation of organoids and 3D tissue models are increasingly used for characterizing drug, toxicity responses and neurodevelopmental disorders. We established here a neuro-toxicogenomic assay by utilizing 'minibrain', a human in vitro 3D brain model system and a low-cost, highly multiplexable RNA-seq methodology (BRB-seq) for screening the effect of trimethyltin chloride (TMT) induced neurotoxicity. We demonstrate that transcriptomic profiling is insightful to the cellular composition and regional identity of the minibrain. Further, we characterize the transcriptomic changes associated with the dose-time neurotoxic response of minibrain upon exposure to TMT. The distinct gene expression changes and molecular candidates identified with our pipeline provides insight to map the key events involved in the adverse outcome pathway of TMT associated neurotoxicity. We identify processes such as endoplasmic reticulum stress, dysregulation of synaptic genes and downregulation of neuron-morphology associated genes upon exposure to TMT. In response to TMT, we identify activation of an early response homeostatic mechanism in minibrain and an interplay of STAT pathways correlating with the dose severity. In this study, we present a neuro-toxicogenomic assay that demonstrates the power of a low-cost transcriptomic screening to study chemical induced neurotoxicity.

show abstract

“…Pershina (Institute of Theoretical and Experimental Biophysics, RAS, Pushchino, Russia) who presented a neurotoxic model of neurodegeneration based on rat treatment with trimethyltin chloride (TMT). This treatment was found to have different effects on expression of various subtypes of mGluRs (mGluR4, mGluR5, and mGluR7) in the hippocampus and prefrontal cortex of rats, which resulted in enhanced cell death in the hippocampus implying a different contribution of individual mGluR subtypes to neurodegeneration and/or neuroprotection (Kamaltdinova et al 2020;Pershina et al 2019).…”

Section: Key Mechanisms and Drug Developmentmentioning

confidence: 99%

Molecular Mechanisms of Cognitive Impairment and Intellectual Disability—Virtual ESN Mini-Conference in Conjunction with the FENS Forum, July 11–15, 2020

et al. 2020

View full text Add to dashboard Cite

Expression of mGlu Receptor Genes in the Hippocampus After Intoxication with Trimethyltin

Cited by 8 publications

References 27 publications

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events

Molecular Mechanisms of Cognitive Impairment and Intellectual Disability—Virtual ESN Mini-Conference in Conjunction with the FENS Forum, July 11–15, 2020

Contact Info

Product

Resources

About