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.

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.

Amantadine increases L-DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats.

We investigated the effect of amantadine on L-DOPA-derived extracellular dopamine (DA) levels and aromatic L-amino acid decarboxylase (AADC) activity in the striatum of rats with nigrostriatal dopaminergic denervation by 6-hydroxydopamine (6-OHDA). Pretreatment with 30 mg/kg amantadine increased the cumulative amount of extracellular DA in the striatum of 6-OHDA-lesioned rats treated with 10 mg/kg benserazide and 50 mg/kg L-DOPA to 250% of that without amantadine (P<0.01). Under pretreatment with 10 mg/kg benserazide, AADC activity after 30 mg/kg amantadine administration was reduced to 43% of controls (P<0.01). Amantadine-induced increase in L-DOPA-derived extracellular DA provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. However, the effect of amantadine on L-DOPA-derived extracellular DA may not be caused by changes in AADC activity.

Rapid change of tonotopic maps in the human auditory cortex during pitch discrimination.

OBJECTIVE: To study early cognitive processes and hemispheric differences in the primary auditory cortex during selective attention. METHODS: We measured auditory evoked magnetic fields (AEFs) to 400 and 4000 Hz tone pips that were randomly presented at the right or left ear. Subjects paid attention to target stimuli during pitch (high or low) or laterality (left or right) discrimination tasks. In the control session, 400 or 4000 Hz tone alone was presented at the left or right ear. We calculated the location and strength of N100m dipole for 400 and 4000 Hz tones, based on the AEFs obtained from the hemisphere contralateral to the stimulated ear. RESULTS: N100m amplitude increased in both hemispheres in pitch or laterality discriminating conditions. N100m latency also shortened during selective attention. The N100m dipole distance between 400 and 4000 Hz tones was enlarged, especially in the right auditory cortex during pitch discrimination task, but was unchanged during the laterality discrimination task. CONCLUSIONS: We conclude that these dynamic changes in the N100m dipole reflect short-term plastic changes in the primary auditory cortex, supporting early selection models. SIGNIFICANCE: This work is the first to disclose short-term plastic changes during pitch discrimination in the human auditory cortex based on the analysis of magnetoencephalography.

Dynamic movement of N100m dipoles in evoked magnetic field reflects sequential activation of isofrequency bands in human auditory cortex.

OBJECTIVE: To investigate spatiotemporal features of the isofrequency bands for 400 and 4000 Hz tones in human auditory cortex and on the hemispheric differences in the arrangement of isofrequency bands. METHODS: We recorded auditory evoked magnetic fields (AEFs) to 400 or 4000 Hz tone pips presented at right or left ear from 31 normal subjects. The dipole location for the N100m sources was successively calculated from the AEFs obtained from the hemisphere contralateral to the stimulated ear. RESULTS: In the right hemisphere, the current sources for 400 and 4000 Hz moved toward the anterolateral direction before the N100m peak, showing parallel arrangement of the isofrequency bands (4000 Hz in medial location). In the left hemisphere, the movement direction of 400 Hz dipoles was anterolateral, while that of 4000 Hz dipoles was lateral. CONCLUSIONS: This difference in the organization of isofrequency bands between right and left auditory cortices reflects distinct functional roles in auditory information processing such as pitch vs. language discrimination. SIGNIFICANCE: This work is the first to disclose isofrequency bands in human auditory cortex based on the analysis of magnetoencephalography.

Dynamic anterolateral movement of N100m dipoles in evoked magnetic field reflects activation of isofrequency bands through horizontal fibers in human auditory cortex.

To analyze the temporal changes in localization of an equivalent current dipole (ECD) for the auditory N100m, we recorded auditory evoked magnetic fields (AEFs) to 400 Hz tone pips presented at the right or left ear. Using a single ECD model, the dipole location for the N100m sources was successively calculated from the AEFs obtained from the hemisphere contralateral to the stimulated ear. We found that the location of the N100m current sources moved dynamically in medio-lateral and postero-anterior directions before the N100m peak. This direction was parallel to the surface of the supratemporal cortex. We propose that the dynamic movement of the N100m dipole reflects spread of intracortical activation through horizontal fibers of pyramidal neurons in the auditory cortex, forming the isofrequency bands in humans.

Rapid induction of serotonergic hyperinnervation in the adult rat striatum with extensive dopaminergic denervation.

The aim of our study was to determine whether serotonergic hyperinnervation is rapidly induced in the striatum of adult rats with extensive dopaminergic denervation. Immunohistochemical study was performed on the brain sections obtained at 2 and 8 weeks after injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The extent of dopaminergic denervation was evaluated as a percentage loss of tyrosine hydroxylase immunopositive neurons in the substantia nigra pars compacta. The immunopositive areas for serotonin (5-HT) in the striatum were measured. In the lesioned rats 97.5+/-0.6% of dopamine neurons were lost. 5-HT immunopositive areas in the striatum were significantly increased both at 2 and 8 weeks after 6-OHDA injection (P<0.01). These results suggest that extensive dopaminergic denervation in adult rats induces rapid serotonergic hyperinnervation in the striatum as early as 2 weeks after lesioning.

Acute cholecystitis and duodenitis associated with Churg-Strauss syndrome.

We describe a patient with acute cholecystitis and duodenitis associated with Churg-Strauss syndrome. A 36-year-old male, who had been healthy, had abdominal pain following high fever. He had marked hypereosinophilia of 17,000/mm3. Radiographs of the chest disclosed a transient infiltrated lesion in the left lower lung. Ultrasonographic and gastroendoscopic examinations revealed acute cholecystitis and duodenitis, respectively. Endoscopic retrograde cholangiopancreatography demonstrated a filling defect suspecting aberrant ascariasis in the common bile duct. The patient suddenly developed distally dominant mononeuritis multiplex, especially in the upper limbs. Muscle biopsy revealed vasculitis of intramuscular arteries with infiltration of eosinophils. These findings fulfilled the diagnostic criteria of Churg-Strauss syndrome. Corticosteroid dramatically resolved the abdominal symptoms. Cholecystectomy and removal of the foreign body were performed. Histological examinations revealed that necrosis of the gallbladder was caused by occlusion due to thrombosed arteries and that the foreign body in the common bile duct was an aggregate of necrotic epithelium of the bile duct wall surrounded by inflammatory cells. Although abdominal complaints rarely appeared as an initial symptom in the patients with Churg-Strauss syndrome, this syndrome should be taken into consideration for an accurate diagnosis when the patients with abdominal pain of unknown origin had eosinophilia, asthma, or allergic rhinitis.

[Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease].

A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson's disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson's disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson's disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone's potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.

Generation of symptomatic palatal tremor is not correlated with inferior olivary hypertrophy.

Although the generation of symptomatic palatal tremor (SPT) is thought to derive from the abnormal activity of hypertrophic inferior olivary neurones, the actual mechanism of SPT has not yet been elucidated. We therefore investigated the relationship between SPT and the pathological process of inferior olivary hypertrophy (IOH). We examined 16 autopsied subjects with cerebrovascular lesions of the dentate-olivary tracts. We analysed the size of the olives, the number of olivary neurones, synaptic, axonal and astrocytic changes in the olives and the clinical course in the subjects. SPT was observed in eight patients, in seven of whom it appeared 1-2 months after interruption of the afferents then progressed to reach a peak approximately 1-2 years from the onset. SPT persisted for the rest of the subjects' lives without decreasing in severity. Neuronal hypertrophic change began 20-30 days after the onset of the causative lesions and reached maximum size, accompanied by prominent astrocytosis and synaptic and axonal remodelling, 6-7 months later. The number of olivary neurones decreased to <10% of that in controls in patients who survived >6 years. Despite the persistence of SPT, both the myelin and the axons of efferent fibres from olivary neurones were severely degenerated in patients who survived several years. Therefore, the appearance of SPT may depend on the hyperactivity of olivary neurones released from inhibitory inputs until the peak of both IOH and SPT. However, the persistence of peak intensity and distribution of established SPT is probably due to both the disturbance of natural rhythmicity in the body and the lack of feedback from the abnormal movement resulting from the dysfunction of the olive.

Effects of benserazide on L-DOPA-derived extracellular dopamine levels and aromatic L-amino acid decarboxylase activity in the striatum of 6-hydroxydopamine-lesioned rats.

Benserazide is commonly used for Parkinson's disease in combination with L-DOPA as a peripheral aromatic L-amino acid decarboxylase (AADC) inhibitor. However, recent studies using intact animals indicate that benserazide acts also in the central nervous system. We determined the influence of benserazide on the central AADC activity in rats with dopaminergic denervation and observed changes in extracellular dopamine (DA) levels after benserazide and L-DOPA administration. First, using in vivo microdialysis technique, we measured extracellular DA levels in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats treated with benserazide and L-DOPA. Second, we measured AADC activity in the striatal tissues after benserazide administration. Although administration of 5, 10 and 50 mg/kg benserazide to 6-OHDA-lesioned rats showed an identical increase in exogenous L-DOPA-derived extracellular DA levels, the time to reach the peak DA levels were significantly prolonged by benserazide dose-dependently. The AADC activity in the denervated striatal tissues showed a significant decrease by 10 mg/kg and 50 mg/kg benserazide. These results suggest that benserazide reduces the central AADC activity in the striatum of rats with nigrostriatal denervation, which leads to changes in the metabolism of exogenous L-DOPA. Central activity of AADC inhibitors should be taken into consideration when they are used both in experimental and clinical studies on Parkinson's disease.

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.