IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network.

We previously reported that interleukin (IL)-6 deficiency potentiates trimethyltin (TMT)-induced convulsive neurotoxicity. The purpose in this study was to investigate the molecular mechanism by which cytokines affect TMT-induced cognitive impairment. To accomplish this, we examined hippocampal changes in Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in relation to cholinergic parameters after TMT treatment in mice genetically deficient in IL-6 (IL-6(-/-)), tumor necrosis factor-α (TNF-α(-/-)), or interferon-γ (IFN-γ(-/-)).

Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice.

Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice.

Background: The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro.

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ.

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments.

Dextromethorphan-induced psychotoxic behaviors cause sexual dysfunction in male mice via stimulation of σ-1 receptors.

Dextromethorphan (DM) is a well-known antitussive dextrorotatory morphinan. We and others have demonstrated that sigma (σ) receptors may be important for DM-mediated neuromodulation. Because an earlier report suggested that DM might affect sexual function and that σ receptor ligands affect signaling pathways in the periphery, we examined whether DM-induced psychotoxic burden affected male reproductive function.

Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo.

We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-α, interferon-γ, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6(-/-) mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6(-/-) mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus.

PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment.

The present study was designed to evaluate the specific role of protein kinase C (PKC) δ in methamphetamine (MA)-induced dopaminergic toxicity. A multiple-dose administration regimen of MA significantly increases PKCδ expression, while rottlerin, a PKCδ inhibitor, significantly attenuates MA-induced hyperthermia and behavioral deficits. These behavioral effects were not significantly observed in PKCδ antisense oligonucleotide (ASO)-treated- or PKCδ knockout (-/-)-mice.

Role of oxidative stress in epileptic seizures.

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models.

Identification of a 42-kDa Group IV cPLA2-activating protein, cPLAPγ, as a GTP-binding protein in the bovine brain.

Brain tissue contains multiple forms of Phospholipase A(2) (PLA(2)) whose activities are involved in intracellular and intercellular signalling related to normal functions such as long-term potentiation, neurotransmitter release, cell growth and differentiation. Among them, we focused on regulatory mechanism of cPLA(2)α (Group IVA cytosolic PLA(2)) in brain tissue. In the present study, we report the identification of a cPLA(2)-activating protein (cPLAP) in the bovine brain.

Neuropsychotoxic and neuroprotective potentials of dextromethorphan and its analogs.

Dextromethorphan (3-methoxy-17-methylmorphinan) has complex pharmacologic effects on the central nervous system. Although some of these effects are neuropsychotoxic, this review focuses on the neuroprotective effects of dextromethorphan and its analogs. Some of these analogs, particularly dimemorfan (3-methyl-17-methylmorphinan) and 3-hydroxymorphinan, have promising neuroprotective properties with negligible neuropsychotoxic effects.

Parishin C attenuates phencyclidine-induced schizophrenia-like psychosis in mice: involvements of 5-HT1A receptor.

Parishin C, a major component of Gastrodia elata BLUME (GE), was purified from GE. Because GE modulates the serotonergic system and the 5-HT(1A) receptor is an important therapeutic target of schizophrenia, we examined whether parishin C affects phencyclidine-induced abnormal behaviors in mice. Phencyclidine-induced abnormal behaviors were significantly ameliorated by parishin C.

Potentiation of methamphetamine neurotoxicity by intrastriatal lipopolysaccharide administration.

Accumulated evidence has indicated that neuroinflammation is one of the important etiologic factors of Parkinson's disease (PD). Earlier studies have employed the inflammogen lipopolysaccharide (LPS) to induce inflammation of dopaminergic neurons. Methamphetamine (MA) dopaminergic toxicity similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity is frequently cited as a model of PD.

Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice.

Microsomal epoxide hydrolase (mEH) and cytochrome P-450 (CYP) ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics. Although CYP has been demonstrated to modulate methamphetamine (METH)-induced behavioral effects, little is known about the role of the mEH gene on these effects. We examined the role of mEH gene expression in METH-induced conditioned place preference and behavioral sensitization by using mEH(-/-) and wild-type (WT) mice.

The activation of ERK1/2 via a tyrosine kinase pathway attenuates trail-induced apoptosis in HeLa cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as an extracellular signal that triggers apoptosis in tumor cells. To characterize the molecular events involved in TRAIL-induced apoptotic signaling, we investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa cell death. Here we show that TRAIL-activated ERK1/2 through a tyrosine kinase-dependent pathway, subsequently elevated anti-apoptotic Bcl-2 protein levels.

Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death.

3-Hydroxykynurenine (3-HK), an endogenous tryptophan metabolite, is known to have toxic effects in brain. However, the molecular mechanism of the toxicity has not been well identified. In this study, we investigated the involvement of MAPK/extracellular signal-regulated kinase (ERK) in the 3-HK-induced neuronal cell damage.

P53 mediates ceramide-induced apoptosis in SKN-SH cells.

Ceramide induces apoptotic cell death in a dose- and time-dependent manner in neuroblastoma SKN-SH cells. Pretreatment with caspase inhibitors blocks cell death, suggesting that a set of caspase activities including caspase 1, as well as caspase 3, are involved in ceramide-induced apoptosis in SKN-SH cells. Treatment with a caspase inhibitor 3 h after ceramide addition did not inhibit cell death, although caspase activity was substantially reduced.

The involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein (MAP) kinase in TRAIL/Apo2L-induced apoptosis.

To determine the apoptotic signaling pathway which tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induced, we investigated the contribution of reactive oxygen species (ROS), p38 mitogen-activated protein (MAP) kinase and caspases in human adenocarcinoma HeLa cells. Here we show that upon TRAIL/Apo2L exposure there was pronounced ROS accumulation and activation of p38 MAP kinase, and that activation of caspases and apoptosis followed. Pretreatment with antioxidants such as glutathione or estrogen attenuated TRAIL/Apo2L-induced apoptosis through a reduction of ROS generation and diminished p38 MAP kinase and caspase activation.