Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions.

BACKGROUND: Similar drugs (e.g. anticonvulsants) have been implicated in the development of two distinct forms of severe cutaneous drug reactions, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). AIM: To investigate immunological alterations and underlying viral infections that could contribute to the variability in the clinical presentations of these diseases. METHODS: We retrospectively analysed clinical variables, serum immunoglobulin levels, numbers of circulating white blood cells, lymphocytes and their subsets, serum levels of several cytokines, and underlying viral infections in both drug reactions, using samples obtained at onset from 9 patients with SJS/TEN and 19 patients with DIHS/DRESS. RESULTS: There were significant differences between the two drug eruptions in the duration of drug intake before onset, the levels of IgG, IgA and IgM, the numbers of circulating white blood cell, lymphocyte, CD3+ T cell and CD8+ T cells, the serum levels of interferon-γ, and the titres of anti-herpes simplex virus IgG at onset. CONCLUSIONS: The difference in the pattern of immune responses shaped in part by previous and underlying viral infections at the time of drug exposure could cause a marked deviation in the pathological phenotype of severe drug eruptions. Elucidating these host factors may provide a basis for therapeutic approaches in patients with severe drug reactions.

An Open-Label Trial of Yokukansan on Sleep Disturbance in Alzheimer's Disease and Other Dementia.

BACKGROUND: An effective hypnotic drug with a low risk of adverse reactions is required for Alzheimer's disease (AD) patients, because the therapeutic interventions to improve sleep quality may help alleviate some symptoms of AD including cognitive function. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of Yokukansan in sleep disturbances in patients with AD and other dementia. DESIGN: An open-label trial. SETTING: Two sites consist of university and hospital in Japan. PARTICIPANTS: Thirteen patients (7 men and 6 women, average age = 76.0 ± 7.2 (mean ± SD) years old) including 12 AD and 1 frontotemporal dementia. INTERVENTION: Treatment with Yokukansan (5-7.5 g/day) was given for 8 weeks. MEASUREMENTS: The primary outcome measure was the Sleep Disorder Inventory (SDI) based on the Neuropsychiatric Inventory, an instrument developed by the Alzheimer's Disease Cooperative Study. Secondary outcome measures included the objective actigraphic evaluations, Neuropsychiatric Inventory-Questionnaire (NPI-Q), MINI-Mental State Examination (MMSE). These assessments were evaluated at baseline, and weeks 4 and 8. RESULTS: After 4 and 8 weeks treatment with Yokukansan, significant improvements were observed in the SDI total score, caregivers' distress score, and NPI-Q total score. In actigraph data, wake after sleep onset (WASO) time (min), was significantly improved. The MMSE score did not change during the treatment. No serious adverse events were caused by YKS. CONCLUSION: The present results suggest that Yokukansan is safe and beneficial in the treatment of sleep disturbances and that it can possibly reduce the burden of care of demented patients.

Presenile dementia with motor neuron disease in Japan. A new entity?

A 61-year-old woman suffered the gradual onset of difficulty with memory, concentration, and cognition at age 58. Progressively more severe dementia was accompanied by muscle wasting and fasciculation prominent in hand and bulbar muscles. An electromyogram and a muscle biopsy specimen demonstrated denervation patterns, and a computerized tomographic scan showed considerable cerebral atrophy. This report reviews cases of presenile dementia with motor neuron disease reported in Japan and discusses the possibility of a new clinicopathologic entity.

Familial occurrence of adult-type neuronal ceroid lipofuscinosis.

The adult type of neuronal ceroid lipofuscinosis (NCL) occurred in a 49-year-old man and his 51-year-old sister. They showed episodic stuporous and psychotic states, mental retardation, generalized convulsions, and ichthyosis vulgaris. At autopsy the woman had excessive accumulation of lipofuscin throughout the CNS. The degree of neuronal lipopigment accumulation was very severe in the neurons of the thalamus, substantia nigra, inferior olivary nuclei, motor nuclei of the brain stem, and cerebral cortex. Mental symptoms, such as stupor, excitement, hallucinations, and delusions, were the predominant clinical manifestations and so were misdiagnosed as schizophrenia. Though the clinical diagnosis of the adult type of NCL (Kufs' disease) is difficult because of its wide variety of manifestations, symptoms such as episodic psychotic and stuporous states accompanied by convulsive disorders with mild neurologic signs may be an indication of this disease.

Sequential changes in AMPA and NMDA protein levels during Fe(3+)-induced epileptogenesis.

Seizure susceptibility is related to enhanced glutamatergic excitatory synaptic transmission with alterations in the expressions of ionotropic glutamate receptors. We wondered if levels of AMPA and NMDA receptor subunits changed following epileptogenesis induced by amygdalar FeCl(3) injection. We used Western blots to measure levels of subunits in the ipsilateral and contralateral hippocampus at various times after FeCl(3) injection into the amygdaloid body. With acute seizures, at +5 days after the injection, levels of GluR1, NMDAR1, and NMDAR2 were markedly increased in both hippocampi, with quantities at least 2-4 times baseline. By +15 and +30 days after injection, when chronic spontaneous seizures were occurring, the levels of GluR2 were increased, while GluR1 and NMDAR1&2A/B were decreased. Increased NMDAR1&2A/B levels at +5 days are consistent with the occurrence of upregulation of NMDA receptor production in the early stages of epileptogenesis. Since GluR2 suppresses glutamate receptor-mediated Ca(2+)-influx, increased expression of GluR2 with development of chronic, recurrent seizures may be a compensatory effect during epileptogenesis from neural responses to propagated seizures.

Sequential changes in glutamate transporter mRNA levels during Fe(3+)-induced epileptogenesis.

Severe head injury in humans can cause recurrent seizures; this form of epilepsy appears to correlate with the occurrence of parenchymal hemorrhage. The injection of ferric cations, one component of hemoglobin, into rat amygdala, causes lipid peroxidation, and recurrent spontaneous seizures. We wondered whether the regulation of glutamate might be perturbed as a result of severe head injury, which might then act as a mechanism of chronic epileptogenesis. Levels of glutamate transporter glutamate-aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), and excitatory amino-acid carrier (EAAC-1) mRNA were measured in ipsilateral and contralateral hippocampi and cerebral cortex removed from rats at 60 min, 24 h, and 5, 15 and 30 days after FeCl(3) injection into the amygdaloid body. While the neuronal transporter EAAC-1 mRNA was elevated bilaterally for up to 30 days following the microinjection that initiated seizures, GLT-1 mRNA, derived from glial cells, returned to basal levels. At 15 and 30 days after injection, however, when the experimental animals were experiencing spontaneous limbic behavioral seizures, GLAST mRNA was down-regulated. Epileptogenesis may correlate with the impairment of glial glutamate transport, leading to an excitation and imbalance of transmitter influences within the hippocampi and cerebral cortex.

Fos expression in neurons immunoreactive for neuronal nitric oxide synthase in the rat paraventricular nucleus after intraperitoneal injection of interleukin-1 beta.

Double immunostaining for Fos and neuronal nitric oxide synthase (nNOS) was used to examine whether nNOS-immunoreactive neurons in the paraventricular hypothalamic nucleus (PVN) are activated to express Fos immunoreactivity by intraperitoneal injection of interleukin-1 beta (IL-1 beta) in the rat. Quantitative analysis revealed that some nNOS-positive PVN neurons are activated by IL-1 beta (4 microg/kg, i.p.) administration, but the majority of the IL-1 beta-activated PVN neurons do not express nNOS and are distributed mainly in the parvocellular part of the PVN.

Methamphetamine-induced Fos expression in the substantia nigra pars reticulata in rats with a unilateral 6-OHDA lesion of the nigrostriatal fibers.

In rats with a unilateral 6-hydroxydopamine (6-OHDA)-induced lesion in the nigrostriatal fibers, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI), which was inhibited by pretreatment with N-methyl-D-aspartate antagonist MK-801 (1 mg/kg, i.p.), not only in the medial striatum contralateral to the lesion but also in the substantia nigra pars reticulata (SNr) ipsilateral to the lesion. Thus, hemispheric asymmetries in FLI were induced by methamphetamine in the medial striatum and the SNr in the 6-OHDA model of turning which may be related to the altered function of glutamatergic transmission.

GABA(A) and GABA(B) receptors modulating basal and footshock-induced nitric oxide releases in rat prefrontal cortex.

Using an in vivo brain microdialysis technique, we measured extracellular levels of nitric oxide (NO) metabolites (NO(x)(-)) in the medial prefrontal cortex (mPFC) upon perfusion of gamma-aminobutyric acid (GABA) receptor antagonists as well as agonists, and also examined the effects of GABA receptor agonists on mild intermittent footshock-induced NO releases in the mPFC in conscious rats. Perfusion of either bicuculline methiodide, a GABA(A) receptor antagonist, or saclofen, a GABA(B) receptor antagonist, through a microdialysis probe resulted in dose-dependent increases in NO(x)(-) levels. Higher-dose perfusion of either muscimol (50 microM), a GABA(A) receptor agonist, or baclofen (250 microM), a GABA(B) receptor agonist resulted in a significant decrease in NO(x)(-) levels. The elevated levels of NO(x)(-) after mild intermittent footshock were attenuated by perfusion of either muscimol (10 microM) or baclofen (50 microM), either of which alone did not affect basal NO(x)(-) levels. These findings are likely to provide helpful clues to our understanding of the inhibitory modulation of basal and footshock-induced NO metabolites releases by GABA(A) and GABA(B) receptors in the mPFC.

Methamphetamine induces fos expression in the striatum and the substantia nigra pars reticulata in a rat model of Parkinson's disease.

In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion in the nigrostriatal pathway, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) not only in the striatum on the intact side but also in the substantia nigra pars reticulata (SNr) on the lesioned side. The methamphetamine-induced hyperexpression of FLI in the SNr on the lesioned side was suppressed by pretreatment with either dopamine D1 receptor antagonist SCH-23390 (0.5 mg/kg, i.p.), D2 receptor antagonist raclopride (2 mg/kg, i.p.) or N-methyl-d-aspartate receptor antagonist MK-801 (1 mg/kg, i.p.), which was concomitant with inhibition of the methamphetamine-induced rotational behavior of each antagonist. However, the hyperexpression of FLI in the SNr was not suppressed by intrastriatal grafts of fetal ventral mesencephalon which could suppress the methamphetamine-induced rotation completely. These results indicate that opposite hemispheric asymmetries in FLI are induced by methamphetamine in the striatum and the SNr in the 6-OHDA rats. It is suggested that the FLIs in the two discrete sites are activated independently by different mechanisms, and furthermore, different neuronal pathways are involved in the methamphetamine-induced rotation and Fos expression in the SNr of 6-OHDA rats.

Differential profiles of nitric oxide and norepinephrine releases in the paraventricular nucleus region in response to mild footshock in rats.

The purpose of this study was to determine whether the application of mild intermittent footshock stress can cause changes in the nitric oxide (NO) and norepinephrine (NE) releases in the hypothalamic paraventricular nucleus (PVN) region and medial prefrontal cortex (mPFC). Extracellular levels of NO metabolites and NE in the PVN region and mPFC were determined using an in vivo brain microdialysis technique in conscious rats. In the PVN region, we demonstrated that perfusion of N-methyl-D-aspartate through a microdialysis probe resulted in a dose-dependent increase in NO metabolite levels, whereas intraperitoneal administration of N(G)-nitro-L-arginine methyl ester produced a dose-dependent reduction in the levels of NO metabolites. The levels of NO metabolites in the PVN region increased after intraperitoneal administration of interleukin-1beta in a dose-dependent manner, as we previously reported. This increase in NO metabolite levels was abolished 60 min after systemic administration of N(G)-nitro-L-arginine methyl ester compared to the vehicle-treated control group. Twenty minutes of intermittent footshock induced NE release but did not induce NO release in the PVN region. On the contrary, in the mPFC, 20 min of intermittent footshock induced both NO and NE releases. The present results reveal different patterns and time courses in NO and NE releases between the PVN region and the mPFC in response to mild intermittent footshock stress. These findings are likely to have helpful suggestions for our understanding of the hypothalamic-pituitary-adrenal axis and the limbic forebrain system response to different kinds of stress.

Dopaminergic transplants suppress L-DOPA-induced Fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease.

We examined the effects of MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and fetal ventral mesencephalic (VM) transplants on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced Fos protein expression in the dopamine (DA)-depleted striatum. Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were produced in young adult female rats and grafting was performed 3 weeks later. Methamphetamine-induced rotational behavior recovered significantly on the 4th week after grafting. Immunohistochemical examinations of c-Fos and tyrosine hydroxylase (TH) were performed 3-4 months after grafting. L-DOPA (100 mg/kg, i.p.) markedly induced Fos-like immunoreactivity (FLI) in the DA-depleted striatum. Pretreatment with a large dose of MK-801 (3-4.5 mg/kg, i.p.) dose-dependently suppressed L-DOPA-induced FLI in the striatum. The stimulatory effect of L-DOPA on c-Fos expression observed within the lesioned striatum was suppressed by fetal VM transplants. It seemed that the graft-induced effect on FLI extended over a considerably larger area than that covered by the graft-derived TH-immunoreactive innervation. Taken together, these findings suggest that glutamatergic modulation is involved in the L-DOPA-induced c-Fos expression in the denervated striatum which is normalized by fetal VM transplants. It also seems likely that VM grafts suppress the L-DOPA-induced expression of transcriptional factors which might be involved in the mechanisms underlying various side effects of chronic L-DOPA therapy.

Serotonergic activity in the rat striatum after intrastriatal transplantation of fetal nigra as measured by microdialysis.

In vivo microdialysis was used to examine the effects of dopaminergic transplants on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their precursors and major metabolites in the denervated rat striatum. Dialysis perfusates were collected from intact 6-hydroxydopamine (6-OHDA) lesion plus sham grafted, and lesion plus fetal substantia nigra (SN) grafted striata. The SN transplants ameliorated the reduction of striatal DA and dihydroxyphenylacetic acid (DOPAC) levels in rats with unilateral 6-OHDA lesions of the mesostriatal pathway. The transplants also increased extracellular levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the denervated striatum. In response to NSD-1015 (an inhibitor of aromatic L-amino acid decarboxylase, AADC), 5-hydroxytryptophan (5-HTP) levels were substantially elevated in the SN grafted striata as compared with those in the sham grafted controls, which continued even after subsequent administration of L-3,4-dihydroxyphenylalanine (L-DOPA, 100 mg/kg i.p.). Immunohistochemical analysis showed hyperinnervation of 5-HT fibers in the grafted striatum, which was consistent with the results of microdialysis experiments. These results indicated that implantation of SN grafts into the 6-OHDA-lesioned striatum of rats induces hyperactivity of 5-HT synthesis, release and metabolism.

Abdominal vagotomy attenuates interleukin-1 beta-induced nitric oxide release in the paraventricular nucleus region in conscious rats.

Nitric oxide (NO) has recently been shown to modulate the hypothalamic-pituitary-adrenal axis response to interleukin-1 beta (IL-1 beta). We measured levels of nitrite (NO2-) and nitrate (NO3-) in the hypothalamic paraventricular nucleus (PVN) region using an in vivo brain microdialysis technique in conscious rats. Intraperitoneally administered IL-1 beta produced a significant increase in both NO2- and NO3- levels in the PVN region. We also examined the possible involvement of the abdominal vagal afferent nerves in this effect. In abdominal-vagotomized rats, the increase was significantly attenuated compared to that in sham-operated rats. Our results suggest that the abdominal vagal afferent nerves are involved in intraperitoneally administered IL-1 beta-induced NO release in the PVN region.

Repeated administration of high dose levodopa enhances hydroxyl radical production in the rat striatum denervated with 6-hydroxydopamine.

We examined whether levodopa (L-DOPA) might increase production of hydroxyl radicals in intact and dopamine-denervated rat striatum. Salicylate trapping combined with in vivo microdialysis provided measurements of 2,3-dihydroxybenzoic acid (2,3-DHBA) as a marker of hydroxyl radical production. Acute administration of high-dose L-DOPA (200, 500 mg/kg, i.p.) did not alter 2,3-DHBA levels in intact striatum or in striatum denervated with 6-hydroxydopamine. On the other hand, L-DOPA administration (200 mg/kg, i.p.) transiently increased 2,3-DHBA in dopamine-denervated striatum of rats after repeated administration of L-DOPA (200 mg/kg, i.p., once daily for 16 days). The results indicated that repeated administration of high dose L-DOPA increased production of hydroxyl radicals in dopamine-denervated striatum.

Dopaminergic transplants alter in vivo activity of tryptophan hydroxylase in the striatum in a rat model of Parkinson's disease.

L-3,4-Dihydroxyphenylalanine (L-DOPA) inhibits the activity of tryptophan hydroxylase (TRH) and thus serotonin synthesis. This inhibitory effect of L-DOPA may be related to some side effects in the patients under L-DOPA therapy. The effects of transplantation of fetal ventral mesencephalon (VM) on extracellular 5-hydroxytryptophan (5-HTP) accumulation was examined by microdialysis as an index of in vivo activity of TRH in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats. In the rat striatum perfused with m-hydroxybenzylhydrazine (NSD-1015; an inhibitor of aromatic L-amino acid decarboxylase), L-DOPA and 5-HTP in dialysate were measured simultaneously. In response to NSD-1015, 5-HTP levels were substantially elevated in the lesion plus VM-grafted striata as compared with those in the lesion plus sham-grafted striata. The results indicate that implantation of dopamine-rich VM grafts into the 6-OHDA-lesioned striatum of rats induces hyperactivity of TRH.

Peripherally administered tetrahydrobiopterin increases in vivo tryptophan hydroxylase activity in the striatum after transplantation of fetal ventral mesencephalon in six hydroxydopamine lesioned rats.

The intraperitoneal administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4), a natural cofactor for tyrosine hydroxylase and tryptophan hydroxylase (TRH), dose-dependently increased the extracellular concentration of 6R-BH4 itself in rat striatum. The concentration was investigated by in vivo microdialysis and measured simultaneously with 5-hydroxytryptophan (5-HTP), a precursor of serotonin, by high performance liquid chromatography with electrochemical detection. The 6R-BH4 (50 mg/kg, i.p.) administration increased the accumulation of 5-HTP as an index of in vivo TRH activity under the inhibition of aromatic L-amino acid decarboxylase by NSD-1015 in the striatum of both normal control and 6-hydroxydopamine lesioned rats with intrastriatal transplants of fetal ventral mesencephalon (VM). The results suggest that TRH in the striatum of both control and VM-grafted rats is activated by 6R-BH4 penetrating into the brain from the blood.

Effects of area postrema lesion and abdominal vagotomy on interleukin-1 beta-induced norepinephrine release in the hypothalamic paraventricular nucleus region in the rat.

Peripherally administered interleukin-1 beta (IL-1 beta) has been shown to increase extracellular norepinephrine (NE) concentration in the paraventricular nucleus (PVN) of the hypothalamus. The present study was carried out using an in vivo microdialysis technique in conscious rats in order to examine the possible involvement of the area postrema (AP) and the abdominal vagal afferent nerves in this effect. Extracellular NE concentrations in the PVN region were measured by high performance liquid chromatography with electrochemical detection. In AP-lesioned or abdominal-vagotomized rats, the NE increase was significantly attenuated compared to that in sham-operated rats; this reduction was greater in abdominal-vagotomized rats than in AP-lesioned rats. The results suggest that the AP as well as the abdominal vagal afferent nerves is involved in intraperitoneal (i.p.) administered IL-1 beta-induced NE release in the PVN region.