Activation of trigeminal nociceptive neurons by parotid PAR-2 activation in rats

To clarify involvement of protease-activated receptor-2 (PAR-2) in parotid pain, we examined whether PAR-2 activation in the parotid gland could activate trigeminal nociceptive neurons in anesthetized rats, by analyzing immunoreactive Fos as a nociceptive marker. Either the PAR-2 agonist SLIGRL-NH2 or capsaicin, injected into the parotid duct, caused expression of Fos in the trigeminal subnucleus caudalis, although the PAR-2-inactive reversed peptide had no such effect. The Fos expression caused by PAR-2 activation was inhibited by ablation of capsaicin-sensitive sensory neurons. Intraductal SLIGRL-NH2 did not increase vascular permeability in the parotid gland. Our data thus reveal that activation of PAR-2 in the parotid gland can cause activation of trigeminal nociceptive neurons via capsaicin-sensitive sensory nerves most probably by a non-inflammatory mechanism.     

Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease

Selective neuronal dysfunction and degeneration are defining features of Alzheimers disease (AD). While the exact mechanism(s) contributing to this selective neuronal vulnerability remains to be elucidated, we hypothesized that the differential expression of metabotropic glutamate receptors (mGluRs) may play a key role in this process since the various mGluR groups differentially regulate neuronal cell death and survival. In the present study, we focused on the metabotropic glutamate receptor 2 (mGluR2), a subtype of group II mGluRs. The mGluR2 is expressed at low levels in pyramidal neurons in age-matched control cases, whereas we found a strikingly increased mGluR2 expression in AD, in a pattern that mirrored both the regional and cellular subtype of neuronal vulnerability to degeneration and neurofibrillary alterations. Immunoblot analysis confirmed the significant increase in the level of mGluR2 in AD compared with age-matched controls. Agonists for group II mGluRs activate extracellular receptor kinase (ERK), a kinase that is chronically activated in vulnerable neurons of AD. ERK is able to phosphorylate tau protein, so the up-regulation of mGluR2 in vulnerable neurons may represent the upstream mediator of abnormal tau phosphorylation in AD. Immunocytochemical examination revealed considerable overlap between mGluR2 and neurofibrillary alterations. Thus, it is likely that mGluR2 represents a novel therapeutic target for AD.     

Deactivation by benzodiazepine of the basal forebrain and amygdala in normal humans during sleep: a placebo-controlled [15O]H2O PET study

OBJECTIVE: The authors' goal was to identify differences in regional brain activity between physiological and benzodiazepine-induced sleep to clarify the brain structures involved in the drug's hypnotic effect. METHOD: Using positron emission tomography, they compared regional cerebral blood flow during non-REM sleep in nine volunteers treated with placebo or triazolam, a short-acting benzodiazepine, in a double-blind, crossover design. RESULTS: Blood flow in the basal forebrain and amygdaloid complexes was lower during non-REM sleep when subjects were given triazolam than when they were given placebo. CONCLUSIONS: The hypnotic effect of the benzodiazepines may be mediated mainly by deactivation of the forebrain control system for wakefulness and also by the anxiolytic effect induced by deactivation of the emotional center.     

Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia

Expression of dopamine receptors (DA-Rs) in astrocytes was examined in vitro and in vivo using primary cultured astrocytes and brain slices from rat basal ganglia. Astrocytes from basal ganglia expressed DA D1-, D3-, D4- and D5-receptors and D4-mediated signal transduction in response to DA, suggesting possible involvement of astrocytes in the pharmacological action of atypical antipsychotic drugs and in DA response in some neurological diseases.     

Resolution of delusional depression after recovery from delirium

Little attention has been given to the effects of delirium on the course of depression. In clinical practice, we sometimes observe delirium brought on incidentally by severe physical illness or therapeutic drugs such as tricyclic antidepressants. Recently, investigators have discussed whether delirium can in fact have a beneficial effect on the course of depression. We present three cases of delusional depression in which depressive symptoms resolved after patients recovered from incidental delirium caused in two cases by medication, and by respiratory distress leading to asphyxiation in the third. We surmise that delirium may create a biological effect similar to that of electroconvulsive therapy (ECT), which is widely hailed as an effective treatment for delusional depression. Retrograde amnesia caused by delirium and the supportive milieu during treatment of the delirium may have a beneficial psychological effect on recovery from delusional depression.     

Identification of a SACS gene missense mutation in ARSACS

The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).     

Expression Levels of Renal Organic Anion Transporters (OATs) and Their Correlation with Anionic Drug Excretion in Patients with Renal Diseases

PURPOSE: Because the urinary excretion of drugs is often decreased in renal diseases, dosage regimens are adjusted to avoid adverse drug reactions. The aim of present study was to clarify the alteration in the levels of renal drug transporters and their correlation with the urinary drug excretion in renal diseases patients. METHODS: We quantified the mRNA levels of human organic anion transporters (hOATs) by real-time polymerase chain reaction and examined the excretion of the anionic drug, cefazolin, in renal disease patients. Moreover, transport of cefazolin by hOAT1 and hOAT3 were examined using HEK293 transfectants. RESULTS: Among four hOATs, the level of hOAT1 mRNA was significantly lower in the kidney of patients with renal diseases than in the normal controls. The elimination constant of cefazolin showed a significant correlation with the values of phenolsulfonphthalein test and mRNA levels of hOAT3. The uptake study using HEK293 transfectants revealed that cefazolin and phenolsulfonphthalein were transported by hOAT3. CONCLUSIONS: These results suggest that hOAT3 plays an important role for anionic drug secretion in patients with renal diseases and that the expression levels of drug transporters may be related to the alteration of renal drug secretion.     

Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome

BACKGROUND: Intravenous administration of magnesium sulphate (MgSO(4)) is a very effective and safe treatment for torsades de pointes (TdP) associated with acquired long QT syndrome (LQTS) in adults. Discussed here is the efficacy of MgSO(4) for TdP in children with congenital and acquired LQTS. METHODS: The optimal MgSO(4) dosage and serum magnesium (SMg) was determined in six consecutive children with TdP; four had congenital LQTS and two had acquired LQTS. A bolus injection of MgSO(4) was given intravenously over 1 to 2 minutes followed by continuous infusion for the next 2 to 7 days. RESULTS: Of the six patients, five responded completely to the initial bolus of 6.1 +/- 4.2 mg/kg (range, 2.3-12 mg/kg). One (a neonate with congenital LQTS) required a total of 30 mg/kg until complete TdP elimination. Continuous infusion was given at rates of 0.3 to 1.0 mg/kg/hr with no recurrence of TdP. SMg concentration was 3.9 +/- 1.0 mg/dL (2.9-5.4 mg/dL) immediately after bolus injection. CONCLUSION: Intravenous MgSO(4) infusion effectively treated TdP in children with LQTS. Optimal bolus dosage, infusion rates and SMg concentration were 3 to 12 mg/kg, 0.5 to 1.0 mg/kg/hr and 3 to 5 mg/dL, respectively.