92 research outputs found
Targeting metabotropic glutamate receptors in the treatment of epilepsy: Rationale and current status
No full textIntroduction: Several drugs targeting the GABAergic system are used in the treatment of epilepsy, but only one drug targeting glutamate receptors is on the market. This is surprising because an imbalance between excitatory and inhibitory neurotransmission lies at the core of the pathophysiology of epilepsy. One possible explanation is that drug development has been directed towards the synthesis of molecules that inhibit the activity of ionotropic glutamate receptors. These receptors mediate fast excitatory synaptic transmission in the central nervous system (CNS) and their blockade may cause severe adverse effects such as sedation, cognitive impairment and psychotomimetic effects. Metabotropic glutamate (mGlu) receptors are more promising drug targets because these receptors modulate synaptic transmission rather than mediate it. Areas covered: We review the current evidence that links mGlu receptor subtypes to the pathophysiology and experimental treatment of convulsive and absence seizures. Expert Opinion: While mGlu5 receptor negative allosteric modulators have the potential to be protective against convulsive seizures and hyperactivity-induced neurodegeneration, drugs that enhance mGlu5 and mGlu7 receptor function may have beneficial effects in the treatment of absence epilepsy. Evidence related to the other mGlu receptor subtypes is more fragmentary; further investigations are required for an improved understanding of their role in the generation and propagation of seizures
Selective activation of group II metabotropic glutamate receptors is protective against excitotoxic neuronal death
No full textWAG/Rij rats show a reduced expression of CB1 receptors in thalamic nuclei and respond to the CB1 receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges
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90547.pdf (Publisher’s version ) (Closed access)Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) receptors.
Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2-month old and “symptomatic” 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3–12 mg/kg, s.c.), given alone or combined with the CB1 receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.).
Results: Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251.
Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 receptors are targeted by novel antiabsence drugs
Activation of grow II metabotropic glutamate receptors increases transforming growth factor beta mRNA expression in vivo
No full textMetabotropic glutamate receptors as drug targets: what's new?
No full textThe question in the title: 'what's new?' has two facets. First, are 'clinical' expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is 'no', because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is 'yes', because mGlu ligands are promising targets for 'new' disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive
ACTIVATION OF GROUP iii METABOTROPIC GLUTAMATE RECEPTORS INHIBITS THE PRODUCTION OF RANTES IN GLIAL CELL CULTURES
No full textThe chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. We examined the possibility that activation of G-protein-coupled metabotropic glutamate (mGlu) receptors regulates the formation of RANTES in glial cells. A 15 hr exposure of cultured astrocytes to tumor necrosis factor-alpha and interferon-gamma induced a substantial increase in both RANTES mRNA and extracellular RANTES levels. These increases were markedly reduced when astrocytes were coincubated with l-2-amino-4-phosphonobutanoate (l-AP-4), 4-phosphonophenylglycine, or l-serine-O-phosphate, which selectively activate group III mGlu receptor subtypes (i.e., mGlu4, -6, -7, and -8 receptors). Agonists of mGlu1/5 or mGlu2/3 receptors were virtually inactive. Inhibition of RANTES release produced by l-AP-4 was attenuated by the selective group III mGlu receptor antagonist (R,S)-alpha-methylserine-O-phosphate or by pretreatment of the cultures with pertussis toxin. Cultured astrocytes expressed mGlu4 receptors, and the ability of l-AP-4 to inhibit RANTES release was markedly reduced in cultures prepared from mGlu4 knock-out mice. This suggests that activation of mGlu4 receptors negatively modulates the production of RANTES in glial cells. We also examined the effect of l-AP-4 on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. l-AP-4 was subcutaneously infused for 28 d by an osmotic minipump that released 250 nl/hr of a solution of 250 mm of the drug. Detectable levels of l-AP-4 ( approximately 100 nm) were found in the brain dialysate of EAE rats. Infusion of l-AP-4 did not affect the time at onset and the severity of neurological symptoms but significantly increased the rate of recovery from EAE. In addition, lower levels of RANTES mRNA were found in the cerebellum and spinal cord of EAE rats infused with l-AP-4. These results suggest that pharmacological activation of group III mGlu receptors may be useful in the experimental treatment of neuroinflammatory CNS disorders
Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the PI-3 kinase pathway.
No full textThe α2δ subunit and absence epilepsy: Beyond calcium channels?
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175325.pdf (Publisher’s version ) (Open Access)Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and has also been found to be associated with T channels. The presence of the α2δ subunit facilitates VSCC activation. Hence, one expects that drugs that bind to, and inhibit the α2δ subunit, e.g. gabapentin and pregabalin, are protective against absence epilepsy and that mice lacking the α2δ subunit are resistant to evoked absence seizures. In contrast, gabapentin and pregabalin are not clinically useful and may even be detrimental in the treatment of absence epilepsy, and ducky mice lacking the α2δ subunit develop absence seizures. This suggests that the α2δ subunit displays functions that go beyond the regulation of VSCCs, and that these functions are involved in the regulation of the cortico-thalamo-cortical network. This viewpoint critically examines the role of the α2δ subunit in the pathophysiology of absence seizures focusing on the potential role of the α2δ ligands, thrombospondins.8 p
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