Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). 2. Subcutaneous administration of PF (2.5 and 5 mg kg(-1)) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg(-1)) on day 8. 3. When given at 1 h after the last dose of MPTP, and then administered once a day for the following 3 days, PF (2.5 and 5 mg kg(-1)) also significantly attenuated the dopaminergic neurodegeneration in a dose-dependent manner. Post-treatment with PF (5 mg kg(-1)) significantly attenuated MPTP-induced proinflammatory gene upregulation and microglial and astrocytic activation. 4. Pretreatment with 0.3 mg kg(-1) 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor (A1AR) antagonist, 15 min before each dose of PF, reversed the neuroprotective and antineuroinflammatory effects of PF. 5. In conclusion, this study demonstrated that PF could reduce the MPTP-induced toxicity by inhibition of neuroinflammation by activation of the A1AR, and suggested that PF might be a valuable neuroprotective agent for the treatment of PD.
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PMID:Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson's disease by activation of adenosine A1 receptor. 1658 33

Parkinson's disease (PD) is characterized by a triad of symptoms (tremor, rigidity, and bradykinesia). Aside from this, emotional deficits are known to be associated with PD. A key structure of emotional processing is the amygdala. Emotional deficits seen in PD might be due to alterations in the catecholaminergic innervation of this limbic structure. We therefore examined whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) applied to C57/BL6 mice (an animal model of PD) affects the density of tyrosine hydroxylase (TH) immunoreactive fibers in the amygdala as it does in the striatum. MPTP treatment caused a prominent reduction in dopamine levels (about -70%) in the striatum (determined by high-performance liquid chromatography and electrochemical detection), accompanied by massive losses of TH-positive fibers in the striatum (-48.3%). Moreover, MPTP treatment caused prominent reductions of TH-positive fiber densities in the basolateral, lateral and central nucleus of the amygdala (about -20%). These results may provide the morphological basis for behavioral studies analyzing altered emotional responses in animal models of PD.
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PMID:MPTP treatment impairs tyrosine hydroxylase immunopositive fibers not only in the striatum, but also in the amygdala. 1690 2

Parkinson's disease is the second most common neurodegenerative disease. It is charaterized by a progressive loss of dopamine (DA) producing neurons in the midbrain, which result in a decline of DA innervations present in the forebrain, in particular, the striatum. The disease leads to appearance of motor symptoms involving akinesia/bradykinesia, gait disturbances, postural imbalance and tremor. Oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor of DA, provides very good symptomatic relief, but this intermittent and pharmacological treatment is compromised by severe side effects, such as the appearance of abnormal involuntary movements. Viral vector-mediated direct gene transfer techniques are currently being explored in order to provide continuous and stable synthesis of DA in the brain. This review focuses on the basic idea of DA replacement, first describing the enzymatic machinery important for DA synthesis and secondly the various alternative strategies pursued in several laboratories. The DOPA delivery strategy, based on the co-transduction of tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) genes, has been shown to be a powerful approach providing a robust behavioral recovery and reversal of side effects of the pulsatile administration of L-DOPA medication. The DA delivery strategy, on the other hand, aims at triple transduction of the TH, GCH1 and aromatic amino-acid decarboxylase (AADC) enzymes, and thereby provide a higher rate of conversion of DOPA to DA. Finally, transduction of AADC alone has been proposed as a means to improve the conversion of peripherally administered L-DOPA. As the basic scientific rationale behind these strategies are well understood and the results of the animal experiments are very encouraging, we are now entering into an exciting phase with increasing momentum toward the first clinical applications using this experimental therapy in patients suffering from PD.
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PMID:Restoration of the striatal dopamine synthesis for Parkinson's disease: viral vector-mediated enzyme replacement strategy. 1743 Jan 30

Parkinson's disease (PD) is a neurodegenerative disease of the brain characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). No clinically proven drugs that may halt or retard the progression of PD have been reported. This study examined the anti-PD effect of a traditional Japanese/Chinese herbal remedy Toki-to (TKT) using mice treated with a neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). TKT showed improvement of MPTP-induced PD-like symptoms (bradykinesia) in a behavioral test (pole test). Histological studies of SNs from these mice demonstrated that TKT had a protective effect on dopaminergic neurons against MPTP neurotoxicity. Real-time RT-PCR analyses of mRNA from SNs demonstrated that expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) genes were decreased by MPTP treatment and that these decreases were reversed by TKT administration prior to MPTP treatment. DNA microarray analyses indicated that TKT per se suppressed gene expression of serum- and glucocorticoid regulated kinase (SGK) that is believed to be a molecule that drives the pathogenesis of PD. Hence, it is suggested that TKT may inhibit the activation of SGK at the transcriptional level and thusmay participate in halting the progression of MPTP-induced neurotoxicity.
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PMID:Toki-to protects dopaminergic neurons in the substantia nigra from neurotoxicity of MPTP in mice. 1748 89

It is well known that the release of glucocorticoids from the adrenal gland is increased in response to many types of stressors and plays a principal role in stress responses. We have shown that the synthesis of prostaglandins (PGs) in the brain is increased under several stress conditions including immobilization (IMO), and that endogenous glucocorticoids counteract this stress-induced PG synthesis. It was also recently reported that IMO damages dopaminergic (DA) neurons in the substantia nigra (SN), which is known to cause symptoms similar to Parkinson's disease (PD). The present study was therefore undertaken to determine the role of glucocorticoids in modulating the signs of PD induced by IMO. The pole test, in which each mouse was placed head upward at the top of a pole and the time taken to turn downward and to arrive on the floor was recorded, and immunohistochemistry for tyrosine hydroxylase (TH) in the SN were performed to evaluate bradykinesia and injury of DA neurons, respectively. Intact and adrenalectomized (ADX) mice were immobilized for 2 h twice, 1 day apart. Both bradykinesia and a decrease in the number of TH-immunoreactive cells in the SN were observed in ADX mice, but not in intact mice, following IMO. These effects of IMO on ADX mice were restored by treatment with corticosterone or indomethacin, a PG synthesis inhibitor. These results suggest that glucocorticoids play a role in preventing the detrimental effect of IMO on nigral DA neurons and resulting bradykinesia, and that this effect of IMO involves PG-mediated mechanisms.
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PMID:The effect of glucocorticoids on bradykinesia induced by immobilization stress. 1834 62

Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.
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PMID:Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. 1883 65

Aggregation and cytotoxicity of misfolded alpha-synuclein are postulated to be crucial in the disease processes of Parkinson's disease (PD) and other synucleinopathies. Mutations in the alpha-synuclein gene in some pedigrees of familial PD have been reported. The mutant alpha-synuclein has been reported to form fibrillar aggregates resulting in biochemical abnormalities that are responsible for the onset of familial PD. Thus, any agent that effectively prevents the development of misfolded and aggregated alpha-synuclein would be a disease modifying therapeutic candidate. We examined the efficacy of sodium 4-phenylbutyric acid (PBA), one of the chemical chaperons, in transgenic (Tg) mice overexpressing human alpha-synuclein containing a double mutation (A30P + A53T). To evaluate the therapeutic efficacy, bradykinesia and motor coordination were assessed using a pole test and a rotarod treadmill task, respectively. After PBA treatment, these motor deteriorations gradually improved. In immunohistochemical examinations, both a loss of tyrosine hydroxylase-positive neurons and an increase of phosphorylated alpha-synuclein in the substantia nigra were inhibited, resulting in no depletion of the striatal dopamine content. These data suggest that PBA might be one of the therapeutic reagents for neurodegenerative disorders.
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PMID:A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P + A53T transgenic mice. 1934 33

The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
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PMID:A highly reproducible rotenone model of Parkinson's disease. 1938 59

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is well known as an exogenous dopaminergic neurotoxin that induces Parkinson's disease-like symptoms. In addition, 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been investigated as endogenous MPTP mimetic compounds that structurally resemble selegiline, a commercially available drug for treating Parkinson's disease. In the present study, we examined the ability of 1,3-dimethyl-TIQ (1,3-diMeTIQ) and 1,3-dimethyl-N-propargyl-TIQ (1,3-diMe-N-proTIQ) to prevent MPTP-induced Parkinson's disease-like symptoms in mice and to prevent 1-methyl-4-phenylpyridinium ion (MPP+, an active metabolite of MPTP)-induced cytotoxicity in vitro, including its structural stereoselectivity. Repeated administration of MPTP induced bradykinesia, a symptom of behavioral abnormality; this was prevented by both 1,3-diMeTIQ and 1,3-diMe-N-proTIQ pretreatments. Pretreatment with 1,3-diMeTIQ did not prevent the MPTP-induced decrease in dopamine content in the striatum or the decrease in the number of tyrosine hydroxylase-positive cells in the substantia nigra. On the other hand, 1,3-diMe-N-proTIQ prevented these Parkinson's disease-like symptoms; in particular, the trans-isomer of this agent showed potent protective effects. However, the ability of the trans-1,3-diMe-N-proTIQ isomer to prevent MPP+-induced PC12 cell death was weaker than that of its cis-isomer. Thus, stereoisomers of 1,3-diMe-N-proTIQ exhibit different effects; cis-1,3-diMe-N-proTIQ inhibits MPP+-induced cytotoxicity while trans-1,3-diMe-N-proTIQ exhibits neuroprotective effects primarily through MPTP-related biological events in mice. These results also indicate the possibility of utilizing, at least in part, the stereoselective efficacy of 1,3-diMe-N-proTIQ against MPTP and/or MPP+-induced adverse states.
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PMID:Preventative effects of 1,3-dimethyl- and 1,3-dimethyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on MPTP-induced Parkinson's disease-like symptoms in mice. 2011 39

Motor activity of mice acutely treated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was monitored for 6 days using behavioral tests which provide complementary information on motor function: the bar, reaction time, drag, stair climbing, grip, rotarod and footprinting tests. These tests consistently disclosed a prolonged motor impairment characterized by akinesia, bradykinesia, speed reduction, loss of coordination and gait patterns. This impairment was associated with approximately 60% loss of striatal dopamine terminals, as revealed by tyrosine hydroxylase immunohistochemistry, and was attenuated by dopaminergic drugs. Indeed, the dopamine precursor, l-dopa (1-10 mg/kg), and the D(3)/D(2) receptor agonist pramipexole (0.0001-0.001 mg/kg) promoted stepping activity in the drag test (a test for akinesia/bradykinesia). The novel nociceptin/orphanin FQ receptor (NOP) antagonist 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101, 0.001-0.1 mg/kg), an analogue of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397), also promoted stepping and synergistically or additively (depending on test) attenuated parkinsonism when combined to dopamine agonists. High doses of l-dopa (100 mg/kg), pramipexole (0.1 mg/kg), Trap-101 and J-113397 (1 mg/kg), however, failed to modulate stepping, worsening immobility time and/or rotarod performance. Low doses of amisulpride (0.1 mg/kg) reversed motor inhibition induced by l-dopa and J-113397, suggesting involvement of D(2)/D(3) receptors. This study brings further evidence for a dopamine-dependent motor phenotype in MPTP-treated mice reinforcing the view that this model can be predictive of symptomatic antiparkinsonian activity provided the appropriate test is used. Moreover, it offers mechanistic interpretation to clinical reports of paradoxical worsening of parkinsonism following l-dopa. Finally, it confirms that NOP receptor antagonists may be proven effective in reversing parkinsonism when administered alone or in combination with dopamine agonists.
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PMID:Dual motor response to l-dopa and nociceptin/orphanin FQ receptor antagonists in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) treated mice: Paradoxical inhibition is relieved by D(2)/D(3) receptor blockade. 2012 26


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