Excitotoxicity: Bridge to various triggers in neurodegenerative disorders

Mehta, A.; Prabhakar, Mayank; Kumar, Puneet; Deshmukh, Rahul; Sharma, Pankaj

doi:10.1016/j.ejphar.2012.10.032

Cited by 576 publications

(432 citation statements)

References 131 publications

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“…However, CB 1 receptors located on glutamatergic terminals are strongly coupled to heterotrimeric G protein signaling (25) and, in fact, participate in the control of important neurobiological processes such as neuronal excitability (22), motor activity (26), feeding behavior (27), and anxiety (28). Our present findings support that this specific pool of CB 1 receptors should be considered a new key player in the excitotoxicity hypothesis of neural disease (29,30). On mechanistic grounds, it is very plausible that, upon intense activation of a glutamatergic projection, glutamate spillover out of the synapse would trigger in the target neuron the activation of the perisynaptic machinery of endocannabinoid generation (5), composed of type 1 metabotropic glutamate receptors (mostly mGluR5), G q/11 proteins, phospholipase C-β, and diacylglycerol lipase-α, thus producing the endocannabinoid 2-arachidonoylglycerol, which would engage presynaptic CB 1 receptors located on the glutamatergic terminal, thereby inhibiting excess excitatory transmission (5) and buffering the potential neurotoxic effects of extrasynaptic NMDA receptors in the postsynaptic neuron (31,32).…”

Section: Discussionsupporting

confidence: 73%

A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity

Chiarlone

Bellocchio

Blázquez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

112

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The CB 1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB 1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB 1 receptor in animal models, the precise pathophysiological relevance of those two CB 1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB 1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB 1 receptors, and (ii) deleting CB 1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB 1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies. neuroprotection | neuromodulation | excitotoxicity E ndocannabinoids are a family of neuron-communication messengers that act by engaging CB 1 cannabinoid receptors, which are also targeted by Δ 9 -tetrahydrocannabinol (THC), the main bioactive component of cannabis. Endocannabinoid signaling serves as a pivotal feedback mechanism to prevent excessive presynaptic activity, thereby tuning the functionality and plasticity of many synapses (1, 2). The CB 1 receptor is the most abundant G protein-coupled receptor in the brain, and is highly expressed in GABAergic terminals of the forebrain (particularly in cholecystokinin-positive and parvalbumin-negative interneurons) (3), where it inhibits GABA release. Functional CB 1 receptors reside as well on terminals of glutamatergic neurons in several brain regions, where they inhibit glutamate release (4). In concert with this well-established neuromodulatory function, the CB 1 receptor protects neurons in many different animal models of acute brain damage and chronic neurodegeneration, which, during recent years, has raised hope about the possible clinical use of cannabinoids as neuroprotective drugs, especially in still unexplored conditions such as Alzheimer's disease, Huntington disease (HD), amyotrophic lateral sclerosis, and stroke (5-7). However, the assessment of the physiological relevance and therapeutic potential of the CB 1 receptor in neurological diseases is hampered, at least in part, by the lack o...

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Section: Discussionsupporting

confidence: 73%

A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity

Chiarlone

Bellocchio

Blázquez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

112

View full text Add to dashboard Cite

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“…Mitochondria plays a central role in energy metabolism and Ca 2+ homeostasis in cells [37][38][39] . The mitochondrial permeability transition (MPT) is considered to contribute substantially to the regulation of normal mitochondrial metabolism and it is regarded as an important mediator of cell death through the opening of a membrane structure known as the mitochondrial permeability transition pore (MPTP) [40,41] .…”

Section: Discussionmentioning

confidence: 99%

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

Elekofehinti

Kamdem

Bolingon

et al. 2013

Asian Pacific Journal of Tropical Biomedicine

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“…It is well established that increased glutamate release can worsen or prolong seizure activity and plays a major role in the persistence of excitotoxicity [28][29][30]. Glutamate receptors are, therefore, also targeted by AEDs, e.g., topiramate (TPM) [31] and perampanel [32].…”

Section: Introductionmentioning

confidence: 99%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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Excitotoxicity: Bridge to various triggers in neurodegenerative disorders

Cited by 576 publications

References 131 publications

A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity

A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

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Excitotoxicity: Bridge to various triggers in neurodegenerative disorders

Cited by 576 publications

References 131 publications

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

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A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity

A restricted population of CB ₁ cannabinoid receptors with neuroprotective activity