Hideto Miwa

Thalamic tremor Case reports and implications of the tremor-generating mechanism

Article abstract-We report two patients with unilateral resting and postural tremor of the upper limb as a delayed manifestation of thalamic stroke. Neuroradiologic examination showed a lesion in the posterolateral thalamic region in both patients, but with no obvious involvement of the brainstem, the cerebellum, or the cerebellar outflow tract to the thalamic ventrolateral nucleus. NEUROLOGY 1996;46: 75-79

Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition

Recent studies have suggested that defects in the ubiquitin-proteasome system (UPS) contribute to the etiopathogenetic mechanisms underlying dopaminergic neuronal degeneration in Parkinsons disease. The present study aims to study the effects of proteasome inhibition in the nerve terminals of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNpc). Following a unilaterally intrastriatal injection of lactacystin, a selective proteasome inhibitor, dopaminergic neurons in the ipsilateral SNpc progressively degenerated with alpha-synuclein-immunopositive intracytoplasmic inclusions. When lactacystin was administered at a high concentration, the striatum was simultaneously involved, and alpha-synuclein-immunopositive extracytoplasmic granules appeared extensively within the SN pars reticulata (SNpr). In addition, during the retrograde neuron degeneration in SN, the level of heme oxygenase-1 immunopositivity, an oxidative stress marker, was markedly increased in SNpc neurons. These results reveal that intrastriatal proteasome inhibition sufficiently induces retrograde dopaminergic neuronal degeneration with abundant accumulation of alpha-synuclein in the SN.

Generalized Convulsions After Consuming a Large Amount of Gingko Nuts

Summary: We report a 36‐year‐old woman, without any past or family histories of epilepsy, who presented frequent vomiting and generalized convulsions. About 4 h before the convulsion, she had consumed ∼70–80 gingko nuts, seeds of Gingko biloba, in an attempt to improve her health. It is important to know that convulsion may be induced if a large amount of gingko nuts is consumed. The neurotoxicity of gingko nuts, particularly their convulsion‐inducing effect, should be recognized.

Recurrent cranial neuropathy as a clinical presentation of idiopathic inflammation of the dura mater: a possible relationship to Tolosa-Hunt syndrome and cranial pachymeningitis

We report 14 patients with idiopathic recurrent cranial neuropathy, in whom multiple cranial nerves were involved recurrently, either at the same or different times, and appeared bilaterally. Oculomotor nerve involvement was most frequent, while the abducens and facial nerves were the next most frequent. Clinical courses were benign and not progressive, and the symptoms responded well to corticosteroids. Ten patients developed Tolosa-Hunt syndrome during the course of their illness. Laboratory findings and CSF were normal. MRI and CT studies were unremarkable, except for an asymmetric appearance of the cavernous sinus in some patients. One patient showed focal hypertrophic pachymeningitis in the posterior fossa in MRI. We discuss the relationship of the idiopathic recurrent cranial neuropathy with disorders characterized by inflammation of the dura mater, such as Tolosa-Hunt syndrome and cranial pachymeningitis.

Differential expression of c-Fos following administration of two tremorgenic agents : harmaline and oxotremorine

The regional distribution of c-Fos expression in the brain after the administration of two tremorgenic agents was studied. In both the harmaline- and oxotremorin-treated rats, c-Fos-positive neurons were extensively distributed in the basal ganglia nuclei and the cerebellum. Additionally, in the harmalinetreated rats, numerous c-Fos-positive neurons were also distributed throughout the inferior olivary nucleus. In the oxotremorine-treated rats, while the inferior olive was not involved, c-Fos was strongly expressed in the neurons of the reticular thalamic nucleus, possibly due to the muscarinic effects of oxotremorine. The present study revealed that the inferior olive is selectively activated in the harmaline-administered animals and that the basal ganglia are involved in both harmaline- and oxotremorine-induced tremors.

Changes in the incidence of amyotrophic lateral sclerosis in Wakayama, Japan

In the 1960s, the incidence of amyotrophic lateral sclerosis (ALS) in the Kozagawa and Koza areas in Wakayama prefecture was much higher than that in other areas of the world. However, between 1980 and 1993, a gradual decrease in the incidence of the disease in these areas was reported. To ascertain whether the decreased incidence has persisted, we conducted a retrospective epidemiological study, and determined the average annual incidence of ALS in Wakayama prefecture from 1998 to 2002. The number of ALS cases encountered during the period was 134 (male 79, female 55). The crude average annual incidence in Wakayama prefecture in total was 2.50 (male 3.08, female 1.99) per 100,000. In the Kozagawa and Koza areas in Wakayama prefecture, where the senility rate rapidly increased in recent years, the average annual incidence of ALS in the present research was 10.56 (male 14.14, female 7.66). When the crude rate was standardized for both age and sex to the Japanese population in 1990, the expected value was 5.24 (male 7.34, female 3.18), which was lower than that of our previous survey. The prevalence in Wakayama prefecture at 31 December 2002 was 11.31 (male 14.40, female 8.53). In Kozagawa and Koza areas, the crude prevalence was 52.81 (male 70.70, female 38.28). These results indicated that the incidence of ALS in Wakayama prefecture, especially for females, steadily decreased compared to that in previous reports. However, a high incidence of ALS persisted among males in Wakayama prefecture, especially in the Kozagawa and Koza areas. Some environmental factors and gender specificity may be related to the decreased incidence of ALS in focus areas.

Oxidative stress and microglial activation in substantia nigra following striatal MPP

The present study aims to study sequential alterations occurring in both dopaminergic neurons and microglia in substantia nigra (SN) following intrastriatal injection of 1-methyl-4-phenylpridium ion (MPP+) in rats. Heme oxygenase-1 (HO-1), a marker of oxidative stress, first appeared in dopaminergic neurons in SN at 1 day post-lesion. Subsequently, microglia in SN exhibited morphological changes indicative of activation. At 7 days post-lesion, those findings increased severity and 7a significant reduction in the number of dopaminergic neurons was observed. The present finding suggests that extensive oxidative stress and secondary-induced neuroinflammation play a relevant role in MPP+-induced retrograde dopaminergic neuron degeneration. We hope that this model will be useful in developing a disease modifying therapy of Parkinsons disease.

Intragastric proteasome inhibition induces alpha-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats

The neuropathological hallmark of idiopathic Parkinsons disease (PD) is dopaminergic neuron degeneration in the substantia nigra. However, it has been suggested that the neurodegenerative process initially may occur in the dorsal motor nucleus of the vagus (DMV). This implies that unidentified environmental toxins or neurotropic pathogens that is capable of passing the mucosal barrier of the gastrointestinal tract might affect the enteric nerve endings of the vagal neurons, possibly resulting in retrograde degeneration of the DMV. The present study aimed to evaluate the effects of proteasome inhibition of the intragastric nerve terminals of the DMV in rats. Following multiple injections of PSI, a selective proteasome inhibitor, or vehicle into the ventral wall of the stomach, the medulla oblongata was studied immunohistologically. In the DMV neurons of rats treated with PSI but not vehicle, alpha-synuclein-immunopositive intracytoplasmic inclusions and activated microglia were observed, predominantly in the left DMV. However, there was no significant loss of neurons. These results suggest that intragastric proteasome inhibition has a retrograde effect on DMV neurons but is insufficient to induce cell death, suggesting no causal linkage between inclusion body formation with proteasome inhibition and neuron death in the DMV. This might also implicate that Lewy body formation in the DMV in PD is possibly related to peroral invasion of environmental toxins that inhibit ubiquitin-proteasome system function.

Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.

Cells of the neural stem cell lineage in the adult subventricular zone (SVZ) respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche) for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc) antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA–mediated signal. We conclude that activation of EphA receptor–mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinsons disease.

Effects of T-type calcium channel blockers on a parkinsonian tremor model in rats

T-type calcium channels are strongly associated with the generation of rhythmic firing patterns in the CNS. Blockers of these channels may have therapeutic potential for treating various types of tremor. The present study aimed to study the effects of a range of T-type calcium channel blockers in a parkinsonian tremor model in rats. We tested the effects of several T-type calcium channel blockers, including zonisamide (ZNS), ethosuximide, lomerizine, amiloride, mibefradil, and NCC 55-0396, a mibefradil derivative, on tacrine-induced tremulous jaw movements (TJMs), an animal model of parkinsonian tremor. Among the tested drugs, only ZNS and NCC 55-0396 significantly suppressed TJMs when given at a non-sedating dose. The transitivity of drugs to the central nervous system (CNS) may at least partially explain their differential anti-TJM effects. However, further studies are necessary to reveal other factors, since ethosuximide failed to show anti-TJM effects despite being known to cross the blood brain barrier. The present results suggest that T-type calcium channels in the CNS may be a suitable target for developing new therapeutic strategies for treating parkinsonian tremor.