Gastrodia Elata Bl Attenuates Cocaine-Induced Conditioned Place Preference and Convulsion, but not Behavioral Sensitization in Mice: Importance of GABA(A) Receptors.

It has been suggested that GABAergic neurotransmission can modulate cocaine dependence and seizure activity. Since Gastrodia elata Bl (GE), an oriental herb agent, has been shown to enhance GABAergic transmission, we examined whether GE affects cocaine-induced seizures, conditioned place preference (CPP), and behavioral sensitization in mice. Treatment with GE (500 or 1000 mg/kg, p.o.) significantly delayed seizure onset time and significantly shortened seizure duration induced by cocaine (90 mg/kg, i.p.). In addition, cocaine (15 mg/kg, i.p.)-induced CPP was significantly attenuated by GE in a dose-dependent manner. However, GE did not significantly alter behavioral sensitization induced by cocaine (15 mg/kg, i.p.). In order to understand whether GABAergic receptors are implicated in GE-mediated pharmacological action in response to cocaine, GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist SCH 50911 were employed in the present study. GE-mediated attenuations on the cocaine-induced seizures and CPP were significantly reversed by bicuculline (0.25 or 0.5 mg/kg, i.p.), but not by SCH 50911 (1.5 or 3.0 mg/kg, i.p.). Therefore, our results suggest that GE attenuates cocaine-induced seizures and CPP via, at least in part, GABA(A) receptor activation.

Gastrodia elata bl attenuates methamphetamine-induced dopaminergic toxicity via inhibiting oxidative burdens.

It has been recognized that Gastrodia elata Bl (GE), an oriental herb medicine, ameliorates various neurological disorders, that GE modulates the monoaminergic and GABAergic systems, and that GE possess antioxidant activities. We examined whether GE affects methamphetamine (MA)-induced striatal dopaminergic toxicity in mice. Treatment with MA (7.5 mg/kg, i.p. × 4) resulted in significant decreases in behavioural activity (as shown by locomotor activity and rota rod performance), dopamine level, tyrosine hydroxylase (TH) activity, and TH protein expression (as evaluated by immunocytochemistry and western blot analysis). In addition, MA treatment showed significant increases in lipid peroxidation [as evaluated by 4-hydroxy-2-nonenal (4-HNE) expression and malondialdehyde formation], protein oxidation (as shown by protein carbonyl expression and its formation), and reactive oxygen species (ROS) formation. Treatment with GE significantly attenuates MA-induced behavioural and dopaminergic impairments, and oxidative stresses in a dose-dependent manner. Our results suggest that GE treatment shows anti-dopaminergic effects in response to MA insult via, at least in part, inhibiting oxidative stresses in the striatum of the mice.

Estrogen attenuates cell death induced by carboxy-terminal fragment of amyloid precursor protein in PC12 through a receptor-dependent pathway.

In the present study, we investigated effects of estrogen on cell death induced by carboxy-terminal fragment of amyloid precursor protein (CT), a candidate causative substance in the pathogenesis of Alzheimer's disease. 17 beta-Estradiol attenuated CT-induced cell death in PC12 cells, whereas 17 alpha-estradiol, nonestrogenic stereoisomer, did not exert any significant protective effect on CT-induced cell death. These results suggest that protective effects of estrogen may be mediated by estrogen receptor (ER) in PC12 cells. To confirm the results, we determined the effects of tamoxifen, an estrogen receptor antagonist. Tamoxifen blocked the protective effects of 17 beta-estradiol, although it did not affect those of 17 alpha-estradiol. Overall, it might be thought that the protective effect of estradiol on CT-induced cell death is achieved by hormonal properties mediated through the estrogen receptor rather than the structural properties as a reducing agent.

C-terminal fragment of amyloid precursor protein induces astrocytosis.

One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

The protective role of HSP90 against 3-hydroxykynurenine-induced neuronal apoptosis.

3-hydroxykynurenine (3HK), an endogenous metabolite of tryptophan in the kynurenine pathway, is a potential neurotoxin in several neurodegenerative disorders. Stabilizing protein structure, heat shock proteins (HSPs) have diverse roles as molecular chaperones to mediate stress tolerance. In the present study, we investigated the possible protective role of HSPs against 3HK induced neuronal cell death. Here we report that 3HK induced in a dose- and time-dependent manner neuronal cell death in neuroblastoma SK-N-SH cells. The cell death showed characteristic apoptotic features such as cell shrinkage, plasma membrane blebbing, chromatin condensation, and nuclear condensation and fragmentation. Furthermore, SK-N-SN cells were protected from 3HK induced cytotoxicity by prior elevation of HSPs expression. Our results show that the protective effect was abolished by HSP90 anti-sense oligonucleotides while not by HSP27 and HSP70 anti-sense oligonucleotides. Also, our result shows that HSP90 effectively inhibits caspases activities leading to the apoptosis. These results suggest that 3HK induces apoptosis in neuroblastoma SK-N-SN cells and that HSP90 is major contributing protein component of protection against 3HK induced apoptosis.