Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.
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PMID:Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats. 921 95

Central adenosine A(2A) receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A(1) receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A(1) and A(2A) dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A(1) and A(2A) receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A(1) and A(2A) agonist-induced increases of intracellular Ca(2+) concentration. ASP5854 ameliorated A(2A) agonist 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l-dihydroxyphenylalanine (L-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A(2A) antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A(1) and A(2A) receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A(2A) antagonism, and also enhances cognitive function through A(1) antagonism.
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PMID:Pharmacological characterization of a novel, potent adenosine A1 and A2A receptor dual antagonist, 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in models of Parkinson's disease and cognition. 1768 18

Previous neurochemical and behavioral studies suggest that muscarinic receptor antagonism has an excitatory effect on the nigrostriatal dopamine (DA) system. Using in vivo extracellular single unit recording, this study examined whether blockade of the muscarinic receptor by scopolamine alters the firing properties of DA neurons in the substantia nigra (SN). Scopolamine was administered either systemically or locally to DA neurons using microiontophoresis. Surprisingly, scopolamine did not cause any significant change in either the firing rate or pattern of the spontaneously active DA neurons. However, systemic injection of scopolamine significantly increased the number of active DA neurons in the SN. Local infusion of scopolamine into the pedunculopontine tegmental nucleus (PPT) mimicked the effect induced by systemically administered scopolamine, significantly increasing the number of active DA neurons without altering the firing rate and pattern. These results suggest that the reported increase in striatal DA release induced by scopolamine is in part mediated by activation of silent nigral DA neurons. The experiments with PPT local infusion further suggest that part of the effect of scopolamine may be due to its blockade of the inhibitory muscarinic autoreceptors on PPT cholinergic cells. The latter effect may lead to activation of quiescent DA neurons by increasing acetylcholine (ACh) release in the SN or in other brain areas providing inputs to DA neurons. Further understanding of the mechanism of action of scopolamine may help us further understand the role of ACh in both the pathophysiology and treatment of DA-related disorders including schizophrenia and Parkinson's disease.
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PMID:Effects of scopolamine on dopamine neurons in the substantia nigra: role of the pedunculopontine tegmental nucleus. 1936 Aug 52

In rats, cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a diketopiperazine, is neuroprotective after ischemic brain injury and also improves motor function in a rat model of Parkinson's disease. Given nootropic actions of diketopiperazines, we investigated the effects of and potential role for acetylcholine neurotransmission in NNZ-2591 on spatial memory after scopolamine-induced amnesia in rats. Adult male Wistar rats were assigned to four groups: saline/water; saline/NNZ-2591; scopolamine/water and scopolamine/NNZ-2591. Morris Water Maze (MWM) tasks were used to determine spatial learning and memory. Thirty minutes prior to each of four daily acquisition trials, rats were intraperitoneally injected with either scopolamine (0.5 mg/kg) or saline. Either NNZ-2591 (30 mg/kg) or water was administered orally (gavages) 10 min after the injection. Immediately after completion of the day 4 acquisition trial a spatial probe trial was performed. The brains were then collected for immunohistochemical analysis. Scopolamine impaired spatial learning and memory compared to saline treated group, particularly in the day 1 acquisition trial. NNZ-2591 did not reverse this deficit, however it significantly improved memory retention by showing more time spent in the correct quadrant. NNZ-2591 also counteracted the scopolamine-induced up-regulation of choline-acetyltransferase positive neurons in the striatum and similarly counteracted the increased synaptophysin density in the hippocampus. Furthermore, a scopolamine-independent antagonistic effect on muscarinic M2 acetylcholine receptors was found after NNZ-2591 treatment, supporting its modulation of acetylcholine neurotransmission. The data suggest that NNZ-2591 prevents scopolamine-induced acute impairment in memory and modulation of acetylcholine neurotransmission may be the mode of action underlying the memory improvement.
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PMID:NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat. 2018 67

Parkinson's disease (PD) is a degenerative, chronic and irreversible condition. Palliative medicine may play an important role in the care of patients with PD to maintain the quality of life. Scopolamine is a non-competitive antagonist at muscarinic acetylcholine receptors, which was used many years ago in the treatment for PD. To the best of our knowledge, there are no previously reported cases of the use of scopolamine for symptom relief at the end of life in patients with PD. The case reported here shows that treatment with a subcutaneous scopolamine was a useful alternative in a terminal cancer patient with severe tremors unable to take oral PD medication.
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PMID:The use of subcutaneous scopolamine as a palliative treatment in Parkinson's disease. 2081 46

A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics. The effects of anticholinergics are mediated by muscarinic receptors of which five subtypes (M(1)-M(5)) exist. Muscarinic M(4) receptors are found at high concentrations in motor parts of the striatum, suggesting a role for muscarinic M(4) receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M(4) receptor in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine in fully backcrossed muscarinic M(4) receptor knockout mice. The drug-induced catalepsy was strongly attenuated, but not abolished, in M(4) knockout mice as compared to wild-type controls. Scopolamine further attenuated the cataleptic response in M(4) knockout mice, suggesting that non-M(4) muscarinic receptors also participate in the anti-cataleptic effects. In conclusion, these data indicate an important role for M(4) receptors in antipsychotic-induced motor side effects and suggest that M(4) receptors could be a target for future pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism.
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PMID:Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor. 2126 1