Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cGMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague-Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline (ip) or MB (ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NO(x)) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NO(x) and striatal cGMP. Furthermore, NO(x) and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NO(x) or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NO(x)-cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development.
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PMID:Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. 1084 Jan 45

Rats treated with iminodipropionitrile develop a neurobehaviour syndrome with dyskinesia. Searching for the molecular correlates, we have examined the expression of selected genes involved in neurotransmission in motor regions using hybridization histochemistry. Frontal cortical and thalamic vasoactive intestinal peptide (VIP) expression, and striatal dynorphin, enkephalin (ENK) and substance P expression were increased. No change in cortical cholecystokinin (CCK), ENK, glutamic acid decarboxylase (GAD) and somatostatin (SRIF) expression, in striatal GAD, SRIF, nitric oxide synthase (NOS) and guanylate cyclase expression, and in thalamic CCK, GAD and thyrotropin-releasing hormone expression was found. NOS expression in the subthalamic nucleus as well as tyrosine hydroxylase, GAD and CCK expression in the substantia nigra were unchanged. These results confirm the involvement of striatal projection neurons in dyskinesia and suggest a novel role for VIP.
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PMID:Expression of neurotransmitter genes in motor regions of the dyskinetic rat after iminodipropionitrile. 1286 38

Constipation affects 15-25% of people. Its mechanisms are various. There are constipations due to intestinal dyskinesia (functional constipation, irritated bowel syndrome), slow transit (colonic inertia), and muscular apparatus discoordination ensuring defecation (dyssynergic defecation). The treatment of different types of constipation uses prokinetics (type 4 serotonin receptor agonists, chlorine channels activators and guanylate cyclase C channel activators) or spasmolytics, among which pinaverium bromide (dicetel) has demonstrated its high efficacy. Biofeedback therapy or surgical techniques may be used. There is a need to prescribe laxatives in any type of constipation. A pathogenetic approach to treating constipation is most efficient. The paper characterizes stimulant, osmotic, volume, and emollient laxatives and agents stimulating the urge to defecate. It also gives the data of meta-analyses evaluating the efficacy of different drug groups. Particular emphasis is laid of the effect of lactulose and its first preparation--duphalac.
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PMID:[Pathogenetic approaches to treating constipations]. 2530 54