n-(1-methylethyl)-1-1-2-trimethylpropylamine and Nerve-Degeneration

Astrocyte activation observed in the MPTP mouse model and Parkinson's disease patients participates in the cascade of deleterious events that ultimately leads to death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The present study aimed to elucidate whether inhibiting astrocyte activation was involved in the protective effects of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener, on MPP+-induced degeneration of dopaminergic neurons. The results showed that Ipt could decrease MPP+-induced TNF-alpha release and p38 MAPK activation in reactive astrocytes. The effects of Ipt were reversed by the mitochondrial KATP blocker, 5-hydroxydecanoate, indicating that mitochondrial KATP channels participate in the regulation of astrocyte activation. Moreover, systematic administration of Ipt could significantly alleviate MPP+-induced behavioural symptoms in motor coordination, the loss of dopaminergic neurons, and the activation of astrocyte and microglia in the SNpc. Together, these findings suggest that Ipt may protect against MPP+-induced degeneration of dopaminergic neurons by inhibiting astrocyte activation and subsequent release of pro-inflammatory factors.

Topics: 1-Methyl-4-phenylpyridinium; Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Brain Stem; Cell Death; Cells, Cultured; Decanoic Acids; Diazoxide; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Ectodysplasins; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hydroxy Acids; Male; Motor Activity; MPTP Poisoning; Nerve Degeneration; Neurons; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Potassium Channel Blockers; Propylamines; Random Allocation; Rats; Rats, Sprague-Dawley; Substantia Nigra; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase

Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-alpha and prostaglandin E2 (PGE(2)). These inhibitory effects of IPT could be reversed by selective mitochondrial K(ATP) (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-alpha and PGE(2). These data strongly suggest that the K(ATP) opener IPT may be a novel and promising neuroprotective drug via inhibiting microglia-mediated neuroinflammation.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Freezing Reaction, Cataleptic; Male; Membrane Potential, Mitochondrial; Microglia; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Propylamines; Rats; Rats, Sprague-Dawley; Rotenone; Tumor Necrosis Factor-alpha

Mounting evidence reveals that ATP-sensitive potassium (K(ATP)) channel openers (KCOs) exert significant neuroprotection in vivo and in vitro in several models of Parkinson's disease (PD). However, the mechanisms are not well understood. In this study, we demonstrated that SH-SY5Y cells expressed mRNA and proteins for Kir6.1, Kir6.2, SUR1 and SUR2 subunits of K(ATP) channels. Moreover, our results showed that 1-methyl-4-phenyl-pyridinium ion (MPP+) induced up-regulation of mRNA for the Kir6.2 subunit and down-regulation of SUR1. It was further found that pretreatment with iptakalim, a novel K(ATP) channel opener, could attenuate increased extracellular glutamate level and decreased cell survival in SH-SY5Y cell culture after exposure to MPP+. Trans-pyrrolidine-2, 4-dicarboxylic acid (t-PDC), a glutamate transporter inhibitor, partially blocked the effect of iptakalim decreasing extracellular glutamate level. Additionally, iptakalim prevented MPP+-induced inhibition of glutamate uptake in primary cultured astrocytes. The beneficial effects of iptakalim on glutamate uptake of astrocytes were abolished by selective mitochondrial K(ATP) (mitoK(ATP)) channel blocker 5-HD. These results suggest (i) K(ATP) channel dysfunction may be involved in the mechanisms of MPP+-induced cytotoxicity and (ii) iptakalim may modulate glutamate transporters and subsequently alleviate the increase of extracellular glutamate levels induced by MPP+ through opening mitoK(ATP) channels, thereby protecting SH-SY5Y cells against MPP+-induced cytotoxicity.

Topics: 1-Methyl-4-phenylpyridinium; Amino Acid Transport System X-AG; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cytoprotection; Down-Regulation; Extracellular Fluid; Glutamic Acid; Humans; Nerve Degeneration; Neurons; Neuroprotective Agents; Neurotoxins; Parkinson Disease; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Propylamines; Receptors, Drug; RNA, Messenger; Sulfonylurea Receptors