Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents.

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice.

Comparison of injuring effects of vesicant, irritant, and nonvesicant anticancer drugs on endothelial cells.

Anticancer drugs are classified as vesicant, irritant, and nonvesicant drugs on the basis of frequency of their vascular disorder. In this study, we compared the injuring effects of three typical anticancer drugs of each class on porcine aorta endothelial cells (PAECs). The concentration inducing 50% cell viability inhibition was lower in the order of vesicant, irritant, and nonvesicant drugs. These results suggest that injuring effects of anticancer drugs on PAECs may be relevant as an indicator of frequency of their vascular disorder, and that this experimental model may be useful for the study of vascular disorder.

Yokukansan enhances pentobarbital-induced sleep in socially isolated mice: possible involvement of GABA(A)-benzodiazepine receptor complex.

In the present study, we investigated the effect of the Kampo medicine Yokukansan (YKS) on pentobarbital-induced sleep in group-housed and socially isolated mice. Socially isolated mice showed shorter sleeping time than the group-housed mice. YKS (300 mg/kg, p.o.) prolonged the pentobarbital-induced sleeping time in socially isolated mice without affecting pentobarbital sleep in group-housed mice. The prolongation of sleeping time by YKS was reversed by bicuculline (3 mg/kg, i.p.) and flumazenil (3 mg/kg, i.p.), but not WAY100635. These findings suggest that the GABA(A)-benzodiazepine receptor complex, but not 5-HT(1A) receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation.

Yokukansan Enhances Pentobarbital-Induced Sleep in Socially Isolated Mice: Possible Involvement of GABA(A) - Benzodiazepine Receptor Complex.

In the present study, we investigated the effect of the Kampo medicine Yokukansan (YKS) on pentobarbital-induced sleep in group-housed and socially isolated mice. Socially isolated mice showed shorter sleeping time than the group-housed mice. YKS (300 mg/kg, p.o.) prolonged the pentobarbital-induced sleeping time in socially isolated mice without affecting pentobarbital sleep in group-housed mice. The prolongation of sleeping time by YKS was reversed by bicuculline (3 mg/kg, i.p.) and flumazenil (3 mg/kg, i.p.), but not WAY100635. These findings suggest that the GABA(A) - benzodiazepine receptor complex, but not 5-HT(1A) receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation.

Depression-like behavior and reduced plasma testosterone levels in the senescence-accelerated mouse.

During aging, levels of testosterone gradually decline in men and low levels of testosterone in aged men are accompanied by increased incidence of depressive disorders. The senescence-accelerated-prone mouse 10 (SAMP10) is well known as an animal model of aging. The purpose of this study was to investigate the motor function, anxiety levels, depression-related emotional responses, attentional function and plasma levels of testosterone and dehydroepiandrosterone (DHEA) in SAMP10. SAMP10 exhibited a significant prolongation of immobility time compared to that of the aged-matched control senescence-accelerated-resistant mouse 1 (SAMR1) in the tail suspension test for measuring depression. Moreover, significant low levels of plasma testosterone but not DHEA were found in SAMP10, and the testosterone levels were inversely correlated with the depression-like behavior. By contrast, we did not observe any significant differences between SAMP10 and SAMR1 in the open-field, rota-rod, elevated plus-maze, marble-burying behavior, or prepulse inhibition test. The results of the present study indicate that testosterone may play an important role in the depression-like behavior in SAMP10.

Ameliorating effects of Kangen-karyu on neuronal damage in rats subjected to repeated cerebral ischemia.

We previously reported that 21-day (14-day pre-ischemic and 7-day post-ischemic) treatment with Kangen-karyu (KGKR) improved spatial memory impairment and hippocampal neuronal death induced by repeated cerebral ischemia (2 x 10-min, 1-h interval) in rats. In the present study, we examined the effect of single and 14-day pre-ischemic KGKR treatment on neuronal damage in the same repeated cerebral ischemia model. Additionally, to determine the mechanisms of neuroprotection by KGKR at glutamatergic neurons, we examined the effects of KGKR on glutamate release induced by repeated cerebral ischemia in vivo, and on cell damage induced by both glutamate and kainate in primary cultured hippocampal neurons in vitro. The 14-day pre-ischemic KGKR (300 mg/kg, oral administration (p.o.)) treatment reduced neuronal damage and astrocyte expression induced by repeated cerebral ischemia. No effect was observed after single pre-ischemic KGKR treatment. Both single and 14-day KGKR treatment decreased glutamate release in the hippocampal CA1 region in intact rats; however, neither pre-ischemic KGKR treatment altered glutamate release during cerebral ischemia. In vitro, KGKR (100-1000 microg/mL) dose-dependently suppressed hippocampal neuronal damage induced by both glutamate (100 microM) and kainate (1 mM). These data suggest neuroprotection with KGKR requires continuous pre-ischemic treatment, and that the mechanisms of protection may be involved in inhibiting the glutamatergic receptors of the post-synaptic neurons.

Neuroprotective effects of Kangen-karyu on spatial memory impairment in an 8-arm radial maze and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia in rats.

In the present study, we investigated the neuroprotective effects of Kangen-karyu (KGK) in a repeated cerebral ischemia model (2 x 10 min, 1-h interval). A 21-day pre- and post-ischemic treatment with KGK (10 - 300 mg/kg) and aspirin (5 mg/kg) improved the spatial memory impairment and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia. However, a 7-day post-ischemic treatment with KGK did not attenuate the spatial memory impairment and neuronal death in this model. To determine the mechanism of action of KGK, we investigated the effects of a 14-day pre-ischemic treatment with KGK on cerebral blood flow in the hippocampal area of the repeated cerebral ischemia model using laser Doppler flowmetry. The 14-day pre-ischemic treatment with KGK increased the cerebral blood flow during reperfusion. These results suggest that a 21-day pre- and post-ischemic treatment with KGK can protect against brain damage caused by cerebral ischemia by increasing the cerebral blood flow in the hippocampal area.

Yokukansan inhibits social isolation-induced aggression and methamphetamine-induced hyperlocomotion in rodents.

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as on that of their caregivers. However, effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD, such as aggression, agitation, irritability, and hallucinations, in a randomized, single-blind, placebo-controlled study. However, the psychopharmacologic effects of YKS remain unexplored. In the present study, we investigated the effects of YKS on social isolation-induced aggressive behavior and methamphetamine- or MK-801-induced hyperlocomotion in rodents. Social isolation markedly induced aggressive behavior in male Wistar rats. Quetiapine at a dose of 10 mg/kg (per os (p.o.)) significantly inhibited this social isolation-induced aggressive behavior. YKS (100, 300 mg/kg, p.o.) also significantly inhibited the aggressive behavior. Moreover, risperidone (0.1 mg/kg, p.o.) significantly inhibited methamphetamine- or MK-801-induced hyperlocomotion in mice. YKS (300 mg/kg, p.o.) inhibited methamphetamine-induced hyperlocomotion, while YKS at the same dose had no effect on MK-801-induced hyperlocomotion. These findings suggest that YKS may be useful for the treatment of aggression and agitation, and that the psychopharmacologic effects of YKS might be mediated, in part, by inhibiting the activity of the dopaminergic system.

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex.

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.

Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive-compulsive disorder.

Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.

Schizandrin reverses memory impairment in rats.

The present study investigated the effect of schizandrin, a component of the fruit of Schizandra chinesis Baill (Fructus Schizandrae), on memory impairment in rats. Scopolamine (0.5 mg/kg, i.p.), a non-selective muscarinic receptor antagonist, markedly impaired spatial memory in an eight-arm radial maze. A higher dose of scopolamine (3 mg/kg, i.p.) also impaired the passive avoidance response. Schizandrin (1 and 10 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of spatial memory. Similarly, schizandrin (1 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of the passive avoidance response. Moreover, in mice, schizandrin (1 and 10 mg/kg, p.o.) enhanced tremors induced by oxotremorine, a muscarinic M(1) receptor agonist. Taken together these findings suggest that schizandrin reverses scopolamine-induced memory impairment, in part, by enhancing cholinergic function, and that schizandrin might be useful for treating memory deficits.

Theanine prevents memory impairment induced by repeated cerebral ischemia in rats.

The present study investigated the neuroprotective effect of gamma-glutamylethylamide (theanine), a component Japanese green tea (Camellia sinensis), on memory impairment induced by twice-repeated cerebral ischemia in rats. Theanine was injected i.p. immediately after the first occlusion. Theanine (0.3 and 1 mg/kg) significantly prevented the impairment of spatial memory in rats subjected to repeated cerebral ischemia, 7 days after the second reperfusion. Moreover, theanine (1 mg/kg) significantly inhibited the decrease in the number of surviving cells in the hippocampal CA1 field in the same rats. These results suggest that theanine prevents memory impairment induced by repeated cerebral ischemia, in part by protecting against neuronal cell death, and that it might be useful for preventing cerebrovascular disease.

Involvement of GABA(A) receptors in the neuroprotective effect of theanine on focal cerebral ischemia in mice.

We investigated the involvement of gamma-aminobutyric acid(A) (GABA(A)) receptors in the neuroprotective effect of gamma-glutamylethylamide (theanine), a component of Japanese green tea, following a 4-h middle cerebral artery (MCA) occlusion in mice. Theanine (1 mg/kg) reduced the size of the cerebral infarct and alterations of NeuN, GFAP, and Iba 1 expression levels at 24 h after MCA occlusion. This neuroprotective effect of theanine was prevented by bicuculline (GABA(A)-receptor antagonist, 10 mg/kg) but not 3-mercaptopropionic acid (glutamate decarboxylase inhibitor). These results suggest that the neuroprotective effect of theanine is mediated, at least in part, by GABA(A) receptors.

Clinical features of selenium deficiency in infants receiving long-term nutritional support.

OBJECTIVE: Selenium deficiency is a known complication in patients requiring long-term nutritional support; however, the clinical features of selenium deficiency in infants have not been completely described. We describe the clinical features of selenium deficiency in infants. METHODS: Six infants with selenium deficiency were studied retrospectively, with a focus on the period of nutritional support, the clinical symptoms, and the chronologic changes in serum selenium concentrations before and after the administration of selenite. RESULTS: The onset of selenium deficiency in five patients occurred at <6 mo of age; selenium deficiency occurred in one patient 14 mo after birth. One patient received parenteral nutrition for 15 mo after birth; the other five patients primarily received an elemental diet for 2-6 mo. In all patients, growth retardation and alopecia with pseudoalbinism were the characteristic symptoms of selenium deficiency. At the time of diagnosis, the serum selenium level in four patients was <2.0 microg/dL and serum selenium levels in two patients were 3.2 and 3.3 microg/dL, respectively. The resolution of hair symptoms corresponded to the level of serum selenium after 1-2 mo and a rapid improvement in growth occurred in all patients after the administration of selenite. CONCLUSION: The early clinical symptoms of selenium deficiency in infants include growth retardation and alopecia with pseudoalbinism, which are reversible if the patients are treated with adequate amounts of selenite. Clinicians who manage infants receiving long-term nutritional support, including an elemental diet, should be aware of the symptoms associated with selenium deficiency.