4/17/2023 0 Comments Flowjo license 10.1r5![]() ![]() This leads to increased GLU release and excessive stimulation of glutamatergic receptors, resulting in excitotoxic damage and cognitive impairment. The blockade of NMDA receptors in gamma-aminobutyric (GABAergic) interneurons, which express calcium-binding protein parvalbumin, generates a hyperglutamatergic condition as a consequence of decreased inhibitory control of excitatory pyramidal neurons. This theory was proposed based on the capacity of N-methyl-D-aspartate (NMDA) GLU receptor antagonists, such as ketamine, to mimic the positive, negative and cognitive symptoms of schizophrenia in healthy individuals and to exacerbate psychotic symptoms and cognitive decline in patients with the disease. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia.Įvidence from pharmacological, postmortem, brain imaging and genetic studies supports the role of glutamatergic dysregulation in schizophrenia. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. ![]() ![]() Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. ![]()
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