The Effects of Ninjinyoeito on Impaired Spatial Memory and Prefrontal Cortical Synaptic Plasticity through α-Amino-3-hydroxy-5-4-isoxazole Propionic Acid Receptor Subunit in a Rat Model with Cerebral Ischemia and ß-Amyloid Injection.

Ninjinyoeito (NYT), a traditional Japanese medicine, is effective for improving physical strength and treating fatigue and anorexia. Recently, a clinical report revealed that NYT ameliorates cognitive dysfunction in Alzheimer's disease (AD) patients, although the mechanisms remain unclear. AD is a neurodegenerative disorder accompanied by a progressive deficit in memory. Current therapeutic agents are largely ineffective in treating cognitive dysfunction in AD patients. In this study, we investigated the effects of NYT on spatial memory impairment in a rat model of dementia. Rats were prepared with transient cerebral ischemia and intraventricular injection of ß-amyloid1-42 for 7 days (CI + Aß). NYT was orally administered for 7 days after cerebral ischemia. We evaluated spatial memory using the Morris water maze and investigated the expression of α-amino-3-hydroxy-5-4-isoxazole propionic acid receptor subunits, the phosphorylation level of glutamate receptor A (GluA)1 at serine sites S831 and S845, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus and prefrontal cortex of CI + Aß rats. In the CI + Aß rats, NYT treatment shortened the extended time to reach the platform. However, NYT did not restore the decrease in the hippocampal GluA1, GluA2, or CaMKII expression but increased prefrontal cortical phosphorylation levels of S845-GluA1 and CaMKII. Therefore, NYT may alleviate spatial memory impairment by promoting glutamatergic transmission involved in the phosphorylation of S845-GluA1 and CaMKII in the prefrontal cortex of CI + Aß rats. Our results suggest that NYT is a valuable treatment for AD patients.

Ninjinyoeito Prevents Onset of Depression-Like Behavior and Reduces Hippocampal iNOS Expression in Senescence-Accelerated Mouse Prone 8 Mice.

Late-life depression is a globally prevalent disorder. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, attenuates depressive symptoms in older patients. However, the mechanisms underlying the antidepressive effect of NYT are unknown. In this study, we investigated the mechanism of the action of NYT using senescence-accelerated mouse prone 8 (SAMP8) mice, which exhibit accelerated aging. SAMP8 mice were treated with NYT starting at 12 weeks of age. Twelve-week-old SAMP8 mice did not show prolonged immobility time in the tail suspension test compared with age-matched SAMR1 mice (normal aging control). At 34 weeks of age, vehicle-treated SAMP8 mice displayed prolonged immobility time compared with SAMR1 mice. NYT-treated SAMP8 mice showed a shorter immobility time than that of vehicle-treated SAMP8 mice. Notably, NYT decreased hippocampal inducible nitric oxide synthase (iNOS) expression in SAMP8 mice. There was no difference in iNOS expression between SAMR1 and vehicle-treated SAMP8 mice. Subchronic (5 days) administration of an iNOS inhibitor, 1400 W, shortened the immobility time in SAMP8 mice. These results suggest that NYT prevents an increase in immobility time of SAMP8 mice by decreasing iNOS levels in the hippocampus. Therefore, the antidepressive effect of NYT in older patients might be mediated, at least in part, by the downregulation of iNOS in the brain. Our data suggest that NYT is useful to prevent the onset of depression with aging.

Kamishoyosan potentiates pentobarbital-induced sleep in socially isolated, ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep disorders are among the most common symptoms in both peri- and post-menopausal women. Kamishoyosan (KSS) is a Kampo medicine prescribed for the treatment of sleep disorders in menopausal women in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: In the present study, we developed a new animal model of menopausal sleep disorders by inducing social isolation stress in ovariectomized mice. Using pentobarbital-induced sleeping time as an index, we aimed to investigate the effects of KSS and involvement of the benzodiazepine receptors. MATERIALS AND METHODS: Eight-week-old, female ddY mice were ovariectomized or subjected to a sham operation (control) and housed in social isolation or groups for 9 weeks. The animals were divided into four groups, group-housed sham-operated, isolated sham-operated, group-housed ovariectomized, and socially isolated ovariectomized. Pentobarbital (50 mg/kg) was administered intraperitoneally (i.p.). Sleeping time was considered the period between the loss of righting reflex and its return (up to 180 min). KSS was administered orally (p.o.) 60 min before the test. Diazepam and flumazenil were administered i.p. 30 and 45 min before the test, respectively. On the day after administration, the mice were euthanized, and their uteri were weighed. RESULTS: Socially isolated, ovariectomized mice had shorter sleeping times than mice in all other groups. In mice with intact ovaries, diazepam (1 mg/kg, i.p.) considerably prolonged the pentobarbital-induced sleeping time, but KSS (30-1000 mg/kg, p.o.) did not. However, KSS (100 mg/kg, p.o.) significantly prolonged the pentobarbital-induced sleeping time in socially isolated ovariectomized mice. The prolongation of sleeping time mediated by KSS was reversed by flumazenil (3 mg/kg, i.p.). CONCLUSIONS: KSS potentiated pentobarbital-induced sleep in socially isolated, ovariectomized mice, and the benzodiazepine receptors are possibly involved in its pharmacological mechanism. These findings suggest that KSS is beneficial for the treatment of menopausal sleep disorders.

Ibudilast suppresses oxaliplatin-induced mechanical allodynia and neurodegeneration in rats.

Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01-10 µM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.