Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that chronic treatment with the angiotensin-converting enzyme inhibitor perindopril increased striatal dopamine levels by 2.5-fold in normal Sprague-Dawley rats, possibly via modulation of the striatal opioid or tachykinin levels. In the present study, we investigated if this effect of perindopril persists in an animal model of Parkinson's disease, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. C57BL/6 mice were treated with the neurotoxin (30 mg/kg/day intraperitoneally) for 4 days and then left for 3 weeks to allow the degeneration of striatal dopaminergic terminals. At this time, the mice exhibited a 40% decrease in striatal dopamine content and an accompanying 46% increase in dopamine D2 receptor levels compared with control untreated mice. The dopamine content returned to control levels, and the increase in dopamine D2 receptor levels was attenuated in mice treated with perindopril (5 mg/kg/day orally for 7 days) 2 weeks after the last dose of MPTP. When the angiotensin-converting enzyme inhibitor was administered (5 mg/kg/day for 7 days) immediately after the cessation of the MPTP treatment, there was no reversal of the effect of the neurotoxin in decreasing striatal dopamine content. Our results demonstrate that perindopril is an effective agent in increasing striatal dopamine content in an animal model of Parkinson's disease.
 ...
PMID:Effect of chronic angiotensin-converting enzyme inhibition on striatal dopamine content in the MPTP-treated mouse. 1038 73

In this study, Met-enkephalin (Met-enk), substance P (SP) and tyrosine hydroxylase (TH) immunostaining was assessed in caudate nucleus biopsies from 15 Parkinson's disease patients who were treated surgically. According to the combination of changes in Met-enk, SP and TH immunostaining, several subgroups of parkinsonian patients were disclosed. Group I: Patients showing low SP and normal Met-enk immunostaining, and variably reduced TH immunoreactivity. Group II: both SP and Met-enk immunostaining were apparently of normal intensity in these PD patients, but they showed the greatest decrease in TH labeling. Group III: PD patients that showed normal SP, very low Met-enk and variably reduced TH immunostaining. Low Met-enk immunostaining tended to correlate with the severity of the disease as judged by higher Unified Parkinson's disease Rating Scale and gait scores. These results suggest that different neurochemical phenotypes may exist among Parkinson's disease patients. Peptidergic deficits should be taken into account for therapeutic intervention.
 ...
PMID:Subgroups of parkinsonian patients differentiated by peptidergic immunostaining of caudate nucleus biopsies. 1042 81

Dopamine and serotonin neurotransmission regulate striatal preprotachykinin messenger RNA levels. In the present study, we investigated serotonin 2A/2C receptor-mediated regulation of preprotachykinin messenger RNA expression in the rat striatum after adult dopamine depletion produced with 6-hydroxydopamine. Significant reductions (46-61% of control values) in preprotachykinin messenger RNA levels were detected by in situ hybridization in rostral, central and caudal regions of the striatum after >85% dopamine depletion. Repeated administration of the specific serotonin2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide, to dopamine-depleted rats completely reversed the reduction in preprotachykinin messenger RNA levels in rostral, central and dorsal-caudal striatal regions. In unlesioned (vehicle-injected) control animals, repeated administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide did not affect preprotachykinin messenger RNA expression in rostral, central and ventral-caudal striatal regions, but decreased preprotachykinin messenger RNA levels in the dorsal-caudal striatal subregion. In addition, serotonin turnover in the dopamine-depleted rostral striatum was significantly increased by 35-45% which is consistent with serotonin hyperinnervation after 6-hydroxydopamine lesions. These data show that the decrease in striatal preprotachykinin messenger RNA after dopamine depletion can be normalized with repeated serotonin2A/2C receptor stimulation. We hypothesize that this serotonin2A/2C receptor regulation of preprotachykinin messenger RNA expression after 6-hydroxydopamine is a consequence of serotonin hyperinnervation, which may include increased striatal serotonin2A/2C receptors, induced by dopamine depletion. We also propose that the serotonin system could be pharmacologically targeted to restore the direct striatal tachykinin pathway in Parkinson's disease.
 ...
PMID:Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease. 1047 49

The interactions existing between substance P- and dopamine-positive neurons, notably in the basal ganglia, suggest that substance P may have therapeutic use in treatment of Parkinson's disease characterized by impaired dopaminergic transmission. The effects of intracerebroventricularly administered substance P were tested on the levels of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex of 6-hydroxydopamine-lesioned rats. Intracerebroventricular injection of 6-hydroxydopamine decreased the levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the brain structures under investigation. Administration of substance P in low dose (0.35 nmol/kg) had no effect on the 6-hydroxydopamine-induced reduction of the dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid contents in the brain. However, treatment with substance P in higher dose (3.5 nmol/kg) increased the concentrations of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex relative to saline-treated group. Additionally, 6-hydroxydopamine lesions significantly increased 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum and nucleus accumbens. Substance P (3.5 nmol/kg) partially reversed lesion-induced increases in 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum, but did not alter these ratios in nucleus accumbens. To test whether substance P fragmentation is responsible for this phenomenon, substance P(5-11), which is one of the main substance P fragments in rat CNS, was administered in equimolar dose. Substance P(5-11) was found to have no effect on the content of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum and nucleus accumbens. In the frontal cortex, substance P(5-11) produced decreases in dopamine levels and increases in homovanillic acid/dopamine ratio. The results of this study suggest that substance P helps to restore dopamine deficit in the brain in an animal model of Parkinson's disease, with the positive effects being more prominent on the nigrostriatal than on the mesocorticolimbic dopaminergic system, but substance P(5-11) is not responsible for this effect.
 ...
PMID:Intracerebroventricular administration of substance P increases dopamine content in the brain of 6-hydroxydopamine-lesioned rats. 1061 67

L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias.
 ...
PMID:[Development of dyskinesias induced by treatment for Parkinson's disease: potential role of first exposure to L-DOPA (or phenomenon of priming)]. 1074 93

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.
 ...
PMID:Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA. 1076 40

In Parkinson's disease a degeneration of dopaminergic neurons of the nigrostriatal pathway is observed. Loss of dopaminergic regulation of striatal neuron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neurons. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordinated movements. This indicates that absence of dopamine in Parkinson's disease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have anti- parkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore the possibility that an A2AR antagonist might reestablish their motor impairment. Interestingly, blockade of A2AR rescues the behavioral parameters altered in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to normal levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia. They also provide evidence that selective A2AR antagonists can exhibit their anti-parkinsonian activities through a nondopaminergic mechanism.
 ...
PMID:Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. 1090 27

Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D(2) dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D(2) dopamine receptor gene allowed us to test these predictions. When compared with their congenic N(5) wild-type siblings, mice lacking D(2) receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D(2) receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D(2) receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D(2) receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D(2) receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D(2) receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways.
 ...
PMID:The indirect basal ganglia pathway in dopamine D(2) receptor-deficient mice. 1097 27

Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.
 ...
PMID:GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets. 1116 68

Neuropeptide Y, cholecystokinin (tetra- and octasulphated peptides) and substance P were measured in lumbar cerebrospinal fluid obtained from patients with various neurologic disorders such as Parkinson's disease, cerebrovascular disorders, multiple sclerosis, tuberculous meningitis and aseptic meningitis. These results are statistically compared with healthy results. The results accumulated showed that the data collected can provide the vital information necessary for designing drug therapy.
 ...
PMID:Variation in cerebrospinal fluid levels of neuropeptide Y, cholecystokinin and substance P in patients with neurological disorders. 1145 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>