cyclic-gmp and Huntington-Disease

Ergotamine and dihydroergotamine show a higher blocking effect towards the dopamine-induced stimulation of adenylate cyclase activity than to the apomorphine-induced stimulation. This could reflect a possible specificity of the compound to dopaminergic receptor. Bromocriptine blocks in a more competitive way the activation of adenylate cyclase induced in vitro by dopamine, but increases the levels of cAMP in rat striatum in vivo. This effect is blocked by haloperidol and reserpine when given together with bromocriptine. On the base of the biochemical observation and various behavioral data the drug has been used in the treatment of parkinsonism with contrasting results and of Huntington's chorea. Moreover, bromocriptine induces a marked decrease of cGMP levels in cerebellum such as haloperidol and chloropromazine while apomorphine and other dopaminergic drugs increase the levels of cGMP. At the dose of 1 mg/kg, bromocriptine as well as DH-ergotoxine markedly reduces the levels of striatal DOPAC.

Topics: Adenylyl Cyclases; Animals; Brain; Cattle; Corpus Striatum; Cyclic AMP; Cyclic GMP; Ergot Alkaloids; Humans; Huntington Disease; Nucleotides, Cyclic; Parkinson Disease; Rats; Receptors, Dopamine

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

Topics: Animals; Basal Ganglia; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Huntington Disease; Mice; Neostriatum; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Positron-Emission Tomography; Pyrazoles; Quinolines; Subthalamic Nucleus; Tritium

Huntington's disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and Hdh(Q7/Q111) mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anxiety; Autopsy; Avoidance Learning; Blotting, Western; Cognition Disorders; Cyclic GMP; Down-Regulation; Female; Hippocampus; Humans; Huntington Disease; Male; Memory; Mice; Mice, Transgenic; Middle Aged; Motor Activity; Nitric Oxide Synthase Type I; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Adenosine Diphosphate; Alzheimer Disease; Brain Chemistry; Cell Communication; Cyclic GMP; Humans; Huntington Disease; Neurotransmitter Agents; Nitric Oxide

Somatostatin, substance P, cyclic AMP and cyclic GMP were determined in the cerebrospinal fluid of patients with Huntington's disease, in first generation relatives of choreic patients and in neurological control patients. Substance P levels were not significantly altered, but somatostatin levels were markedly decreased both in affected patients and symptom-free offspring. Cyclic AMP was decreased only in patients with advanced stages of the disease while cyclic GMP was normal. Evidence is discussed which may support a role of somatostatin deficiency in the pathophysiology of chorea.

Topics: Adult; Aged; Brain; Cyclic AMP; Cyclic GMP; Female; Humans; Huntington Disease; Male; Middle Aged; Somatostatin; Substance P