Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.
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PMID:Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry. 214 28

N-Methyl-D-aspartate (NMDA), phencyclidine (PCP), and quisqualate receptor binding were compared to benzodiazepine, gamma-aminobutyric acid (GABA), and muscarinic cholinergic receptor binding in the putamen and cerebral cortex of individuals with Huntington's disease (HD). NMDA receptor binding was reduced by 93 percent in putamen from HD brains compared to binding in normal brains. Quisqualate and PCP receptor binding were reduced by 67 percent, and the binding to other receptors was reduced by 55 percent or less. Binding to these receptors in the cerebral cortex was unchanged in HD brains. The results support the hypothesis that NMDA receptor-mediated neurotoxicity plays a role in the pathophysiology of Huntington's disease.
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PMID:NMDA receptor losses in putamen from patients with Huntington's disease. 284 62

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.
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PMID:Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. 901 83

The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenous substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and "open" state, but not when it is in the inactive or "closed" state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed.
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PMID:Imaging the PCP site of the NMDA ion channel. 1469 91

Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson's and Huntington's diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre-frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg(-1) daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs-treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder.
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PMID:Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice. 2283 53

Pridopidine is in clinical trials for Huntington's disease treatment. Originally developed as a dopamine D2 receptor (D2R) ligand, pridopidine displays about 100-fold higher affinity for the sigma-1 receptor (sigma-1R). Interestingly, pridopidine slows disease progression and improves motor function in Huntington's disease model mice and, in preliminarily reports, Huntington's disease patients. The present study examined the anti-amnesic potential of pridopidine. Thus, memory impairment was produced in mice by administration of phencyclidine (PCP, 10 mg/kg/day) for 10 days, followed by 14 days' treatment with pridopidine (6 mg/kg/day), or saline. Finally, novel object recognition performance was assessed in the animals. Mice receiving PCP and saline exhibited deficits in novel object recognition, as expected, while pridopidine treatment counteracted PCP-induced memory impairment. The effect of pridopidine was attenuated by co-administration of the sigma receptor antagonist, NE-100 (10 mg/kg). Our results suggest that pridopidine exerts anti-amnesic and potentially neuroprotective actions. These data provide new insights into the therapeutic potential of pridopidine as a pro-cognitive drug.
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PMID:Pridopidine Reverses Phencyclidine-Induced Memory Impairment. 2969 29