Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently reported several neurochemical alterations, measured at perinatal and peripubertal ages, in the maturation of nigrostriatal dopaminergic neurons following perinatal hashish exposure. In the present work, we tried to undertake whether these neurochemical changes during ontogeny: a) were accompanied by changes of motor behavior, the main neurobiological process regulated by nigrostriatal dopaminergic neurons; and b) persisted in adulthood, leading to disturbances in the expression of an adult motor activity. To this end, two different experiments were performed. In the first, we examined, by using an actimeter, the ontogeny of spontaneous locomotor activity in immature male and female rats born from mothers perinatally exposed to hashish extract. Results showed a complete absence of significant changes in locomotor activity in females, whereas males presented a constant trend to decrease, although never statistically significant, at all ages studied as a consequence of the perinatal cannabinoid exposure. In the second experiment, we evaluated neurochemical indices--dopamine (DA) and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents, tyrosine hydroxylase (TH) activity, and number and affinity of D1 and D2 dopaminergic receptors in the striatum--and behavioral parameters--spontaneous locomotor activity and spontaneous and induced stereotypic behavior--both indicating nigrostriatal dopaminergic activity, in adult female and male rats perinatally exposed to hashish extract. Results were as follows. The spontaneous locomotor activity, measured in the actimeter, was not affected by perinatal hashish exposure in both adult males and females. This was also seen in an open-field test as measured by total number of sector crossings. However, when differentiated between internal and external sectors hashish-exposed males presented a higher number of external crossings than controls, which did not appear in females. Moreover, several induced stereotypic behaviors, such as self-grooming and shaking induced by water spraying, were also altered by hashish treatment in a sexually dimorphic manner, whereas the number of spontaneous rears and self-grooms, measured in the open-field test, was unchanged. Thus, the frequency of water spraying-induced self-grooming was significantly increased in both males and females perinatally exposed to hashish, although the increase was more marked in males (200.4%) than females (121.2%). In addition, the frequency of shaking was also markedly increased in males but remained unchanged in females. These behavioral effects were paralleled by modifications in striatal neurochemical parameters. Thus, there was a significant increase in the DOPAC/DA ratio, indicating increased presynaptic activity, in females perinatally exposed to hashish, but compensated by a lower density of D1 receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Motor behavior and nigrostriatal dopaminergic activity in adult rats perinatally exposed to cannabinoids. 790 90

We measured the concentrations of the monoamines, their precursors, and their metabolites, and the activity of choline acetyltransferase (ChAT) in basal ganglia and cortical regions of postmortem brains from cases with histologically verified pure Alzheimer's disease (AD), AD with diffusely distributed Lewy bodies (Lewy body variant [LBV]), and normal controls. Dopamine and homovanillic acid (HVA) were severely depleted in basal ganglia of the LBV cases but were not significantly altered in pure AD cases; tyrosine hydroxylase levels in putamen were also significantly reduced in LBV but not AD cases. These reductions in basal ganglia dopamine and HVA suggest that LBV cases have a level of dopamine depletion similar to Parkinson's disease (PD). Additionally, ChAT activity in caudate and norepinephrine concentration in putamen were significantly reduced in the LBV group, which may have contributed to the absence of resting tremor and the milder presentation of parkinsonian features in this group compared with classic PD. In frontal, parietal, and temporal cortex, activity of ChAT in the LBV group was significantly reduced compared with controls and lower than in pure AD.
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PMID:Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies. 810 20

The progressive degeneration of dopamine neurons observed in idiopathic Parkinson's disease was mimicked by injecting low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons, on a chronic basis. Five Papio papio baboons were treated on two different regimens (chronic intravenous administration at weekly intervals for 20-21 months or, daily MPTP treatment for five days followed five to six months later by chronic weekly injections for 5-21.5 months). All animals were assessed for motor symptoms during and after neurotoxic treatment. Both regimens invariably resulted in the appearance of a progressive and irreversible syndrome characterized by action and resting tremor, cogwheel rigidity, postural impairments, hypokinesia and bradykinesia. In some animals, symptoms of resting tremor and rigidity initially restricted to one side of the body became bilateral within a few months of treatment. Subtle abnormalities that may be found in idiopathic Parkinson's disease such as alterations of the blink reflex response were also noted. Neuropathological examination of caudate nucleus, putamen, substantia nigra and ventral tegmental area in brain sections stained for tyrosine hydroxylase showed a typical uneven striatal dopamine fibre loss and a neuronal depletion in the dopaminergic mesencephalic cell groups that reproduce those observed in idiopathic Parkinson's disease. Immunocytochemical observations and behavioural data show that chronic rather than acute MPTP injection regimens can replicate most of the neuropathological and the clinical features typical of idiopathic Parkinson's disease, possibly by increasing the ability of this neurotoxin to target specific subpopulations of mesencephalic dopaminergic neurons.
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PMID:Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons. 846 5

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
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PMID:Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset. 918 19

The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.
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PMID:Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease. 924 19

We sought to identify a clonidine withdrawal syndrome in conscious rats by investigating the effects of a single injection of the specific alpha2-adrenergic antagonist atipamezole (1.5 mg/kg i.p.) after chronic treatment with the alpha2-adrenergic agonist clonidine (200 microg/kg per day via osmotic mini-pump for 7-10 days). Rats treated chronically with clonidine followed by atipamezole injection (clonidine-atipamezole) demonstrated dramatic behavioral effects including shaking, vigorous digging, and whole-body seizure-like movements. Control groups (saline-saline, clonidine-saline and saline-atipamezole) showed no overt unusual behavioral effects following injection. The brains of the clonidine-atipamezole group showed massive c-Fos expression (especially in di- and telencephalon) while the other groups showed either background levels of c-Fos-immunopositive cells (saline-saline and clonidine-saline groups) or a slight increase over background in selected areas (saline-atipamezole group). Maps of c-Fos-immunolabeled cells were generated at five representative coronal planes for each treatment group. C-Fos-immunopositive cells were counted in three representative brainstem structures (locus coeruleus, nucleus of the solitary tract, rostral ventrolateral medulla (RVL)) and in three regions of the thoracic spinal cord (dorsal horn, intermediate zone and ventral horn). In the three brainstem structures the number of c-Fos-positive cells was elevated 8-10-fold in the clonidine-atipamezole group compared to the other groups. No other treatment group was significantly different from the saline-saline group. An increased number of c-Fos-positive neurons was also noted in the dorsal horn and intermediate layers of the thoracic spinal cord in the clonidine-atipamezole group compared to a sham-operated atipamezole-injected group. In the RVL, 59% of c-Fos-positive cells contained alpha2A-adrenergic receptor-like immunoreactivity in clonidine-atipamezole treated (withdrawing) rats. In addition, one-third of the tyrosine hydroxylase (TH)-immunopositive cells in RVL were also c-Fos-positive in clonidine withdrawing rats where no TH-positive cells were also c-Fos-positive in RVL of control groups. Atipamezole injected 10 min after a single injection of clonidine (200 microg/kg, i.p.) produced no behavioral effect and did not increase c-Fos expression in brainstem. Injection of the opiate antagonist naltrexone (100 mg/kg, i.p.) in rats chronically treated with clonidine did not elicit behavioral effects or result in increased c-Fos expression in brainstem. In conclusion, administration of the selective alpha2-antagonist atipamezole to rats chronically treated with the alpha2-adrenergic agonist clonidine triggers a powerful withdrawal syndrome associated with massive CNS expression of c-Fos protein. The intensity of the withdrawal syndrome indicates that chronic exposure to alpha2-adrenergic receptor agonists produces strong dependence.
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PMID:Atipamezole-precipitated clonidine withdrawal induces c-Fos expression in rat central nervous system. 929 96

Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation) is an autosomal dominant, childhood onset, postural dystonia and the first hereditary basal ganglia disorder whose causative enzyme and gene defect were clarified. The initial symptom is unilateral pes equinovarus with marked diurnal fluctuation. Progression becomes slower after mid-teens and stationary after thirties. Postural tremor may occur after 10 years of age, especially after thirties. Parkinsonian resting tremor action and torsion dystonia. and disturbed locomotion do not occur. L-Dopa shows marked and sustained effect without side effects. F-Dopa PET and [11C] raclopride PET of over 20-year-old cases are normal. Deficiency of GTP cyclohydrolase I (GCH-I) was suggested from low CSF biopterin and neopterin. Mutation of GCH-I gene and decreased GCH-I were clarified as etiology. Twenty-five mutations discordant among families have been found. Autopsy of a gene proven case revealed decreased striatal tyrosine hydroxylase (TH) and dopamine (DA) in ventral striatum where direct pathway is predominant. Decreased GCH-I causes decreased tetrahydrobiopterin (BH4), TH and DA in nigrostriatal (NS) terminal. The lowest affinity of BH4 to TH causes selective involvement of DA. Postural dystonia is caused by decreased TH and DA affecting D1-direct pathway. Thalamic ventrolateral and pedunculo-pontine nuclei are spared. Diurnal fluctuation of symptoms is due to diurnal fluctuation of TH and DA at NS-DA terminal. Decreased DA to below 20% of normal, shown by polysomnographical studies, and its physiological age related decremental changes in NS-DA terminal underlies characteristic clinical course. High D2 receptor before early thirties masks D1 related hypertonus and manifest progression before 20 years of age. Other pteridine abnormalities also cause dopa responsive postural dystonia with diurnal fluctuation. A case of juvenile parkinsonism without dystonia showed decreased TH in dorsolateral putamen where indirect pathway is predominant. These suggest that decreased TH due to decreased BH4 involves D1-direct pathway causing dystonia, and decreased TH itself involves D2-indirect pathway causing parkinsonism.
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PMID:[Segawa disease]. 957 70

We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism. Two to four weeks after transplantation, the monkeys initiated a progressive recovery of mobility with reduction of tremor and bradykinesia and restoration of fine motor abilities on the contralateral side. Apomorphine injections induced rotations toward the side of the transplant. Functional recovery was accompanied by the survival of tyrosine hydroxylase-positive (TH-positive) grafted glomus cells. A high density of TH-immunoreactive fibers was seen reinnervating broad regions of the ipsilateral putamen and caudate nucleus. The nongrafted, contralateral striatum remained deafferented. Intrastriatal autografting of carotid body tissue is a feasible technique with beneficial effects on parkinsonian monkeys; thus, this therapeutic approach could also be applied to treat patients with Parkinson's disease.
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PMID:Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen. 1023 Jul 94

Parkinson's disease (PD) is characterized by progressive neuronal loss associated with Lewy bodies in many subcortical nuclei leading to multiple biochemical and pathophysiological changes of clinical relevance. Loss of nigral neurons causing striatal dopamine deficiency is related to both the duration and clinical stages (severity) of the disease. The clinical subtypes of PD have different morphological lesion patterns: a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation. b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex. Rest tremor in PD is associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network suggesting an increased functional activity of thalamo-motor projections. In essential tremor, no significant pathomorphological changes but overactivity of cerebello-thalamic loop have been observed. c) In the akinetic-rigid forms of multisystem atrophy, degeneration is more severe in the lateral SNZC with severe loss of calbindin-IR cells reflecting initial degeneration of the striatal matrix in the caudal putamen with transsynaptic degeneration of striatonigral efferences that remain intact in PD. This fact and loss of striatal D2 receptors--as in advanced stages of PD--are reasons for negative response to L-dopa substitution. These data suggest different pathophysiological mechanisms of the clinical subtypes of PD that have important therapeutic implications. d) Involvement of extranigral structures in PD includes the mesocortical dopaminergic system, the noradrenergic locus coeruleus, dorsal vagal nucleus and medullary nuclei, serotonergic dorsal raphe, nucleus basalis of Meynert and other cholinergic brainstem nuclei, e.g. Westphal-Edinger nucleus (controlling pupillomotor function), posterolateral hypothalamus and the limbic system, e.g. amygdaloid nucleus, part of hippocampal formation, limbic thalamic nuclei with prefrontal projections, etc. Damage to multiple neuronal systems by the progressing degenerative process causing complex biochemical changes may explain the variable clinical picture of PD including vegetative, behavioural and cognitive dysfunctions, depression, pharmacotoxic psychoses, etc. Future comparative clinico-morphological and pathobiochemical studies will further elucidate the pathophysiological basis of specific clinical symptoms of PD and related disorders providing a broader basis for effective treatment strategies. Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and other subcortical neuronal systems leading to striatal dopamine deficiency and other biochemical deficits related to the variable clinical signs and symptoms of the disorder. (ABSTRACT TRUNCATED)
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PMID:Post mortem studies in Parkinson's disease--is it possible to detect brain areas for specific symptoms? 1037 Sep 1

Hereditary progressive dystonia with marked diurnal fluctuation or the strictly defined dopa-responsive dystonia (HPD/DRD) is an autosomally dominantly inherited dystonia caused by abnormalities of the gene of the GTP cyclohydrolase I (GCH 1) located on the 14q22. 1-q22.2. The heterozygotic gene abnormality induces partial decrement of tetrahydrobiopterin (BH4) and affects synthesis of tyrosine hydroxylase (TH) rather selectively. The reduction of TH exists at the terminals of the nigrostriatal (NS) dopamine (DA) neuron, predominantly in the ventral area of the striatum and disfacilitates the D1 receptor-striatal direct pathway. This consequently disinhibit the inhibitory efferent pathways and develops postural dystonia via the particular descending pathways to the reticulospinal tract and postural tremor via the ascending pathways to the ventralis lateralis (VL) nucleus of the thalamus. This also inhibits the efferents to the superior colliculus, and affects voluntary saccade but spares that to the pedunculo-pontine nucleus (PPN) preserving locomotive movement clinically. The DA-D2 receptors, the striatal indirect pathways or the efferent connecting to these pathways are not involved in the pathophysiology of HPD/DRD. So parkinsonian plastic rigidity, parkinsonian resting tremor, cogwheel rigidity or levodopa induced dyskinesia are not observed. In some patients, particularly in compound hetereozygotes, there are symptoms suggesting the involvement of serotonergic neurons or those thought to be caused by exaggeration of DA-D2 receptors. Neuropathologically there is no degenerative changes. Clinical laboratory examinations suggest that levels of TH and DA activities are around 20% of the normal values throughout the course of illness. Therefore, the age-dependent clinical course, marked progression in the first one and one half decades, its subsiding in the third decade and almost stationary course from the fourth decade are just the reflection of age-related decremental variation of the TH activities at the terminal of the normal NS-DA neuron. The diurnal fluctuation is also the reflection of circadian oscillation of the TH activities at the terminal. Functional maturation of the striatal indirect pathways in the first one and one half decades and developmental decremental variation of the DA-D2 receptor in the first three decades also reflect in the age-dependent variation of symptoms by modulating the background tone of muscle. The later functional development of the ascending efferents of the basal ganglia to the thalamus, may cause the postural tremor which appears in the second decade and becomes predominant in the fourth decade. Early decrease of TH due to deficiency of BH4 in HPD/DRD also affects the DA-D4 receptor of the tuberoinfundibular DA neuron and cause stagnation of increase of body length in childhood. With normal preservation of the fundamental function of the NS-DA neuron, levodopa, by replacing the DA content at the terminal, alleviates the motor symptoms completely and the effects sustain without any side effects. Levodopa also improves the short body length, if it is administrated before puberty. Up to now 60 mutations have been detected in the GCH 1 gene. The locus of mutation differs among families except for two pare of families with different ethnic background which showed identical mutations. Experimentally, one abnormal heterozygotic gene decreased the production of the enzyme to less than 50%, e.g. some below 20% and others around 30-40%, which clinically as symptomatic patients and asymptomatic carriers, respectively. Other experiments show dominant negative effects which differ among families or the loci of mutation. These might be the background for developing the intra-familial variation, that is, in some there is anticipation, and in the other the symptoms and clinical course are identical or vary in a family without any relation to the generation. (ABSTRACT TRUNCATED)
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PMID:Hereditary progressive dystonia with marked diurnal fluctuation. 1098 64


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