Prenatal folate deficiency impairs sociability and memory/recognition in mice offspring.

Folate is essential for the normal growth and development of the fetus. Folic acid supplementation during the fetal period affects postnatal brain development and reduces the incidence of mental disorders in animal and human studies. However, the association between folate deficiency (FD) during pregnancy and developmental disorders in children remains poorly understood. In this study, we investigated whether prenatal FD is associated with neurodevelopmental disorders in offspring. ICR mice were fed a control diet (2 mg folic acid/kg diet) or a folate-deficient diet (0.3 mg folic acid/kg diet) from embryonic day 1 until parturition. We evaluated locomotor activity, anxiety, grooming, sociability and learning memory in male offspring at 7-10 weeks of age. No differences were found in locomotor activity or anxiety in the open field test, nor in grooming time in the self-grooming test. However, sociability, spatial memory, and novel object recognition were impaired in the FD mice compared with control offspring. Furthermore, we measured protein expression levels of the NMDA and AMPA receptors, as well as PSD-95 and the GABA-synthesizing enzymes GAD65/67 in the frontal cortex and hippocampus. In FD mice, expression levels of AMPA receptor 1 and PSD-95 in both regions were reduced compared with control mice. Moreover, NMDA receptor subunit 2B and GAD65/67 were significantly downregulated in the frontal cortex of prenatal FD mice compared with the controls. Collectively, these findings suggest that prenatal FD causes behavioral deficits together with a reduction in synaptic protein levels in the frontal cortex and hippocampus.

TRPV1 mediates the anticonvulsant effects of acetaminophen in mice.

OBJECTIVE: Acetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown. METHODS: This study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models. RESULTS: Repeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect. CONCLUSION: These findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol-kindled mouse models and TRPV1 mediates the anticonvulsant action.

Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the alpha(7) nicotinic acetylcholine receptor in Wistar rats.

Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-Fos protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-Fos-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA.

Evaluation of topical external medicine for 5-fluorouracil-induced oral mucositis in hamsters.

Oral ulcerative mucositis is a common and painful toxicity associated with chemotherapy for cancer. Current treatment for chemotherapy-induced oral mucositis is largely palliative, and no adequate treatment with conclusive evidence exists. The purpose of this study was to evaluate the potential effectiveness of the topical external medicines used in clinical settings, and the authors investigated the effects of 1% azulene ointment, 0.12% dexamethasone ointment, and polaprezinc-sodium alginate suspension on an animal model for oral mucositis induced by chemotherapy. Oral mucositis was induced in hamsters through a combination treatment of 5-fluorouracil and mild abrasion of the cheek pouch. Each drug was administered topically to the oral mucosa of hamsters, and the process of healing of damaged oral mucositis was examined by measuring the size of the mucositis. Azulene ointment did not reduce the size of the mucositis compared with the vaseline-treated control group. Polaprezinc-sodium alginate suspension significantly improved the recovery from 5-fluorouracil-induced damage. In contrast, local treatment with dexamethasone exacerbated the mucositis markedly. These results suggested the healing effect of polaprezinc-sodium alginate suspension and the risk of steroids to severe oral mucositis induced by chemotherapy.

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors.

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05-1 mg kg(-1), s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5-5 mg kg(-1), s.c.), an alpha(7) nicotinic receptor antagonist, nor dihydro-beta-erythroidine (0.5-2 mg kg(-1), s.c.), an alpha(4)beta(2) nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01-0.2 mg kg(-1), s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg(-1), s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg(-1), s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg(-1)) was eliminated by mecamylamine (1 mg kg(-1), i.p.), but not by hexamethonium (10 mg kg(-1), i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg(-1), s.c.). However, dihydro-beta-erythroidine (1 and 2 mg kg(-1), s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central alpha(7) nicotinic receptors.