Cabergoline, a long-acting dopamine agonist, attenuates L-dopa-induced dyskinesia without L-dopa sparing in a rat model of Parkinson's disease.

Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.

Effects of Aging on Levo-Dihydroxyphenylalanine- Induced Dyskinesia in a Rat Model of Parkinson's Disease.

BACKGROUND: It remains unclear why patients with young-onset Parkinson's disease more often develop levo-dihydroxyphenylalanine (L-dopa)-induced dyskinesia (LID) and have a more severe form than patients with old-onset Parkinson's disease. Previous studies using animal models have failed to show young-onset Parkinson's disease enhances LID. OBJECTIVES: To evaluate the association of age at dopaminergic denervation (onset age) and initiation of L-dopa treatment (treatment age) with LID development in model rats. METHODS: We established rat models of young- and old-lesioned Parkinson's disease (6-hydroxydopamine lesions at 10 and 88 weeks of age, respectively). Dopaminergic denervation was confirmed by the rotational behavior test using apomorphine. Rats in the young-lesioned group were allocated to either L-dopa treatment at a young or old age, or saline treatment. Rats in the old-lesioned group were allocated to either L-dopa treatment or saline group. We evaluated L-dopa-induced abnormal involuntary movements during the 14-day treatment period. We also examined preprodynorphin mRNA expression in the striatum (a neurochemical hallmark of LID) and the volume of the medial globus pallidus (a pathological hallmark of LID). RESULTS: LID-like behavior was enhanced in L-dopa-treated young-lesioned rats compared with L-dopa-treated old-lesioned rats. Preprodynorphin mRNA expression was higher in L-dopa-treated young-lesioned rats than in in L-dopa-treated old-lesioned rats. The volume of the medial globus pallidus was greater in L-dopa-treated young-lesioned rats than in L-dopa-treated old-lesioned rats. Treatment age did not affect LID-like behavior or the degree of medial globus pallidus hypertrophy in the young-lesioned model. CONCLUSION: Both dopaminergic denervation and L-dopa initiation at a young age contributed to the development of LID; however, the former may be a more important factor.

An autopsy case of early-stage amyotrophic lateral sclerosis with TDP-43 immunoreactive neuronal, but not glial, inclusions.

Phosphorylated transactivation response DNA-binding protein 43 kDa (p-TDP-43)-immunoreactive neuronal and glial cytoplasmic inclusions are a histopathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43. We report an autopsy case of lower motor neuron-predominant ALS in a 47-year-old Japanese man who committed suicide 5 months after onset. Histopathologically, neuronal loss was restricted to the anterior horn of the spinal cord, and no obvious neuronal loss was noted in the motor cortex or brainstem motor nuclei. Bunina bodies were found in the spinal anterior horn cells and the facial and hypoglossal nuclei. Immunohistochemically, p-TDP-43-immunoreactive neuronal, but not glial, cytoplasmic inclusions were frequently found in the spinal anterior horn and facial and hypoglossal nuclei, and rarely in the motor cortex. We considered the present case to be an example of lower motor neuron-predominant ALS. p-TDP-43-immunoreactive aggregates in neurons, but not in glial cells, may be an early-stage pathology of ALS.

Evaluation of cerebral blood flow in older patients with status epilepticus using arterial spin labeling.

INTRODUCTION: Although older patients with status epilepticus (SE) have a high mortality rate and poor outcome, it is difficult to perform emergent electroencephalography (EEG) to diagnose SE in community hospitals. Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can rapidly assess cerebral blood flow (CBF). Further, ASL can detect increased CBF in the ictal period. Therefore, ASL may be a useful tool for diagnosing SE in older patients. However, its effectiveness in this population is unknown. METHODS: We retrospectively investigated differences in CBF abnormalities between older patients (≥70 years) and non-older patients (<70 years) with SE using ASL. Participants were diagnosed with convulsive status epilepticus (CSE) or non-convulsive status epilepticus (NCSE) based on symptoms, brain MRI, and EEG. RESULTS: ASL detected CBF abnormalities in 40% of older patients with CSE or NCSE. Rates of CBF abnormalities in older patients were not significantly different compared with that in non-older patients. CONCLUSIONS: ASL did not detect a higher rate of CBF abnormalities in older patients, but may help physicians diagnose SE in older patients in a community hospital setting if emergent EEG cannot be immediately performed.

Morphologic changes of dendritic spines of striatal neurons in the levodopa-induced dyskinesia model.

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa-induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa-induced dyskinesia model, we used 6-hydroxydopamine-lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa-induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa-induced dyskinesia.

Giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

We describe an unusual case of myasthenia gravis. Our patient had been diagnosed as having myasthenia gravis with thymoma at the age of 64 years, and died of acute respiratory failure at the age of 80 years. Post mortem examination revealed CD8-positive lymphocytic infiltration with numerous giant cells in the skeletal muscles and myocardium. Immunohistochemical and ultrastructural studies revealed that there were two types of giant cells: histiocytic and myocytic in origin. Furthermore, both types of giant cells were immunopositive for proteins implicated in the late endosome and lysosome-protease systems, suggesting that endocytosis may be the key mechanism in the formation of giant cells. The present case, together with a few similar cases reported previously, may represent a particular subset of polymyositis, that is, giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

Drebrin immunoreactivity in the striatum of a rat model of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia has been suggested to result from maladaptive plasticity at corticostriatal synapses. Synaptic plasticity is based upon morphologic changes of dendritic spines. To elucidate whether the morphologic changes of spines occur in the striatum of rat models of levodopa-induced dyskinesia, we examined immunoreactivity of drebrin, an actin-binding protein localized in dendritic spines of excitatory synapses, using 6-hydroxydopamine-lesioned rats repeatedly treated with levodopa. The cross-sectional area of drebrin-immunoreactive organelles, putative spines, in the dopamine-denervated striatum of the levodopa-induced dyskinesia model was greater than that of the Parkinson's disease model. Immunoelectron microscopic examinations confirmed that drebrin-immunoreactive spines became enlarged in the dopamine-denervated striatum of the levodopa-induced dyskinesia model, but not in the Parkinson's disease model. These results suggest that the development of levodopa-induced dyskinesia is associated with enlargement of dendritic spines at corticostriatal excitatory synapses.

Amyotrophic lateral sclerosis with demyelinating neuropathy.

Amyotrophic lateral sclerosis (ALS) with demyelinating polyneuropathy is a rare condition. We describe two ALS patients with demyelinating neuropathy. Immunomodulatory therapies brought slight symptomatic benefits to the patients, but the treatments could not halt the progression of ALS. Chance coincidence of the two diseases is unlikely in view of the low prevalence. ALS, mainly consisting of progressive axonal degeneration, might show temporal demyelinating features of peripheral nerves both electrophysiologically and pathologically. The pathomechanism for the demyelination in ALS remains to be elucidated.

Venous cerebral infarction in a patient with peripheral hemodialysis shunt and occlusion of the left brachiocephalic vein.

Intracranial venous congestion is a rare condition in hemodialysis patients with central venous occlusion. We report a patient with cerebral venous infarction resulting from high reflex flow into the cranium induced by an arteriovenous hemodialysis shunt in the arm and occlusion of the brachiocephalic vein. This case illustrates that abnormal extracranial venous circulation should be considered when cerebral venous congestion is assumed to produce neurologic symptoms in patients with an arteriovenous shunt.

An unusual case of chronic relapsing tetanus associated with mandibular osteomyelitis.

A 55-year-old man underwent radiation therapy due to malignant lymphoma of the neck. Eight years after the therapy he developed tetanus. It appears that the radiation therapy resulted in mandibular necrosis, and that this lesion may have been the infectious focus of tetanus. Treatment with penicillin G was very effective in the acute stage, and chronic administration of metronidazole prevented relapse of the disease. However in spite of injections of tetanus toxoid, symptoms of tetanus returned when the administration of metronidazole was discontinued because the infectious focus could not be completely removed. This is the first report of chronic relapsing tetanus associated with radiation-induced mandibular osteomyelitis, and demonstrates that tetanus can occur due to mandibular focus but the chronic administration of metronidazole can prevent relapse.

A small trinucleotide expansion in the TBP gene gives rise to a sporadic case of SCA17 with abnormal putaminal findings on MRI.

A Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradual changes in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, and displayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not only showed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted images. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding protein gene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, giving rise to early-onset SCA17.

Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter.

To determine the role of norepinephrine transporter in reuptake of L-DOPA-derived extracellular DA in the DA-denervated Parkinsonian striatum, we examined extracellular DA levels in the striatum of 6-hydroxyDA-lesioned rats that received L-DOPA (50 mg/kg with 12.5 mg/kg of benserazide) and L-DOPA plus desipramine (25 mg/kg), a selective norepinephrine reuptake inhibitor, using in vivo microdialysis. The pretreatment with desipramine increased levels of extracellular DA derived from administrated L-DOPA in the DA-denervated striatum. This study provides evidence that L-DOPA-derived DA is taken up by the norepinephrine transporter, instead of the dopamine transporter, in the striatum with dopaminergic denervation. This result suggests that the norepinephrine transporter could be a promising target in the treatment for Parkinson's disease.

[A case of brain nocardiosis successfully treated with minocycline].

A 60-year-old man with surgically treated nocardia pyothorax was referred to our hospital since he became drowsy. Brain MRI revealed multiple brain abscesses. His cerebrospinal fluid (CSF) showed increase in polymorphonuclear cells and decrease in glucose. Since he was allergic to sulfamethoxazole * trimethoprim, ceftriaxone and then minocycline were given. Minocycline resulted in dramatic improvement of neurological symtoms, MRI findings and CSF cell count. PCR analysis of 16S ribosomal DNA using his resected thoracic wall revealed that nocardia from his tissue was strain IFM0860. Strain IFM0860 nocardia was found to be sensitive to minocycline but not to sulfamethoxazole * trimethoprim and ceftriaxone. Intravenous administration of minocycline was followed by three-year per os administration of minocycline during which he had no recurrence of brain abscess. Thus, brain nocardiosis could be successfully treated with appropriate antibiotics. The lesson from the present case is that identification of the type of nocardia by PCR analysis of 16S ribosomal DNA could help accomplish tailor-made antibiotic therapy.

A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease.

Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinson's disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinson's disease.

Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus.

Recent studies suggest that glutamate plays a pivotal role in the processing of sensory information in the spinal cords of patients with diabetic neuropathy. However, the specific glutamate receptors that that are involved have yet to be determined. We therefore conducted a study to characterize the expression of messenger RNAs (mRNAs) coding for subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and N-methyl-d-aspartate (NMDA) receptors and for metabotropic glutamate receptors (mGluRs) in the dorsal horn of the lumbar segment of the spinal cord in a rat model (streptozotocin [STZ]-induced) of diabetic neuropathy. The levels of mRNAs coding for AMPA receptor subunits, GluR1, GluR2, and GluR3, were significantly increased in all layers (laminae I-V) of the dorsal horn in diabetic (STZ-injected) rats compared to control (vehicle-injected) rats. The hybridization signals for NR2A mRNA and NR2B mRNA were significantly elevated in the deep layer of the dorsal horn of diabetic rats. In diabetic (STZ-induced) rats, the levels of expression of mGluR1 mRNA and mGluR5 mRNA were significantly increased in all layers of the dorsal horn. These results suggest that abnormal expression of multiple glutamate receptors is involved in the development of diabetic neuropathy and that glutamate receptors are promising targets in the treatment of this disorder.

Upregulation of striatal adenosine A2A receptor mRNA in 6-hydroxydopamine-lesioned rats intermittently treated with L-DOPA.

To determine whether the adenosine A2A receptor might play a role in L-DOPA-induced dyskinesia in Parkinson's disease, we analyzed changes in the expression of A2A receptor mRNA in response to intermittent treatment with L-DOPA in rats with dopaminergic denervation by 6-hydroxydopamine (OHDA) infusion into the medial forebrain bundle. Intermittent treatment with L-DOPA increased A2A receptor mRNA levels in the dopamine-depleted striatum of 6-OHDA-lesioned rats exhibiting behavioral sensitization to L-DOPA. These results suggest that A2A receptor activation is associated with the development of motor complications induced by L-DOPA treatment.

Hypertrophy of medial globus pallidus and substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA: implication for L-DOPA-induced dyskinesia in Parkinson's disease.

The medial globus pallidus plays a crucial role in generation of L-DOPA-induced dyskinesia in patients with Parkinson's disease. The 6-hydroxydopamine-lesioned rat exhibiting behavioral sensitization to L-DOPA is one useful animal model for examining L-DOPA-induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA were examined. Intermittent L-DOPA treatment induced hypertrophy of the lesioned-side of medial globus pallidus and substantia nigra reticulata of 6-hydroxydopamine-lesioned rats with behavioral sensitization to L-DOPA. Additionally, coadministration of a 5-HT1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin with L-DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L-DOPA in 6-hydroxydopamine-lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L-DOPA-induced dyskinesia in patients with Parkinson's disease.