n-(1-methylethyl)-1-1-2-trimethylpropylamine and Disease-Models--Animal

The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1β and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1β and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.

Topics: Animals; Blood Pressure; Cell Hypoxia; Disease Models, Animal; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Interleukin-10; Interleukin-1beta; KATP Channels; Lung; Male; Nitric Oxide Synthase Type III; Platelet Endothelial Cell Adhesion Molecule-1; Propylamines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Trachea

Depression is a serious mental disorder in the world, but the underlying mechanisms remain unclear and the effective cures are scarce. Iptakalim (Ipt), an ATP-sensitive potassium (K-ATP) channel opener that can cross the blood-brain barrier freely, has been demonstrated to inhibit neuro-inflammation and enhance adult hippocampal neurogenesis. But it is unknown whether Ipt is beneficial to therapy of depression by modulating neurogenesis and neuro-inflammation. This study aimed to determine the potential antidepressant efficacy of Ipt in a chronic mild stress (CMS) mouse model of depression. We showed that treatment with Ipt (10 mg/kg/day, i.p) for 4 wk restored the decrease of sucrose preference and shortened the immobile time in forced swimming tests (FST) and tail suspension tests (TST) in CMS model mice. We further found that Ipt reversed the CMS-induced reduction of the adult hippocampal neurogenesis and improved cerebral insulin signalling in the CMS mice. Furthermore, Ipt negatively regulated nod-like receptor protein 3 (NLRP3) expression and, in turn, inhibited microglia-mediated neuro-inflammation by suppressing the activation of NLRP3-inflammasome/caspase-1/interleukin 1β axis in the hippocampus of CMS mice. Taken together, our findings demonstrate that Ipt plays a potential antidepressant role in CMS model mice through regulating neuro-inflammation and neurogenesis, which will provide potential for Ipt in terms of opening up novel therapeutic avenues for depression.

Topics: Animals; Antidepressive Agents; Body Weight; Bromodeoxyuridine; Cell Count; Corticosterone; Cytokines; Depression; Disease Models, Animal; Food Preferences; Freezing Reaction, Cataleptic; Hindlimb Suspension; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neurogenesis; Propylamines; Stress, Psychological; Sweetening Agents; Swimming

Hypoxic pulmonary hypertension (HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries. The aim of specific therapies for hypoxic pulmonary hypertension is to reduce pulmonary vascular resistance, reverse pulmonary vascular remodeling, and thereby improving right ventricular function. Iptakalim, a lipophilic para-amino compound with a low molecular weight, has been demonstrated to be a new selective ATP-sensitive potassium (K(ATP)) channel opener via pharmacological, electrophysiological, biochemical studies, and receptor binding tests. In hypoxia-induced animal models, iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Furthermore, iptakalim has selective antihypertensive effects, selective vasorelaxation effects on smaller arteries, and protective effects on endothelial cells, but no effects on the central nervous, respiratory, digestive or endocrine systems at therapeutic dose. Our previous studies demonstrated that iptakalim inhibited the effects of endothelin-1, reduced the intracellular calcium concentration and inhibited the proliferation of pulmonary artery smooth muscle cells. Since iptakalim has been shown safe and effective in both experimental animal models and phase I clinical trials, it can be a potential candidate of HPH in the future.

Topics: Animals; Antihypertensive Agents; Calcium; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; KATP Channels; Myocytes, Smooth Muscle; Propylamines; Pulmonary Artery

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

We investigated the effects of iptakalim, a new ATP-sensitive potassium channel (K(ATP)) opener providing endothelial protection, on the progression of cardiac hypertrophy to failure in a rat model of pressure overloading caused by abdominal aortic banding (AAB). Endothelial dysfunction is central to cardiac hypertrophy and failure induced by pressure overload. It would be useful to clarify whether iptakalim could prevent this.. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, evidence of left ventricular hypertrophy (LVH), and transition to heart failure. LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These could be prevented by treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg for 6 weeks. Progression to cardiac failure, demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial and B-type natriuretic peptide mRNA, could also be prevented. The downregulated nitric oxide signalling system was enhanced, whereas the upregulated endothelin signalling system was inhibited, resulting in normalization of the balance between these two systems.. Iptakalim protected the endothelium and prevented progression of cardiac hypertrophy to failure induced by a pressure overload.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Heart Rate; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Male; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Ventricular Remodeling

The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (KATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of KATP channel openers is available. We hypothesized that pretreatment with a KATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new KATP channel opener, which is selective for SUR2 type KATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood-brain barrier, water content, Na+ and Ca2+ concentration, and activities of Na+,K+-ATPase, Ca2+-ATPase and Mg2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K(ATP) channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K(ATP) channels, suggesting a new therapeutic strategy for stroke treatment.

Topics: Animals; Animals, Newborn; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cell Count; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Electrolytes; Electron Microscope Tomography; Endothelial Cells; Hypoxia, Brain; KATP Channels; Male; Membrane Proteins; Neuroglia; Neurons; Neuroprotective Agents; Occludin; Propylamines; Rats; Rats, Wistar

It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats.. In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid.. These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Angiotensins; Animals; Cells, Cultured; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension; Hyperuricemia; KATP Channels; Kidney; Kidney Diseases; Male; Nitric Oxide; Oxonic Acid; Propylamines; Rats; Rats, Sprague-Dawley; Urate Oxidase; Uric Acid; Xanthine Oxidase

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

Our previous studies revealed that activation of mitochondrial ATP-sensitive potassium channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive potassium-channel opener, and diazoxide, a selective mitochondrial ATP-sensitive potassium-channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium-channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive potassium channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Catalepsy; Decanoic Acids; Diazoxide; Disease Models, Animal; Dopamine; Hydroxy Acids; Levodopa; Male; Motor Activity; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Parkinsonian Disorders; Potassium Channel Blockers; Potassium Channels; Propylamines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotenone; Substantia Nigra

The function of ATP-sensitive potassium (KATP) channels in nigrostriatal pathway in Parkinson's disease (PD) was studied by employing a novel KATP channel opener iptakalim (Ipt). Apomorphine-induced rotation behavior test and microdialysis experiment were carried out in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Behavior test showed that systemic administration of Ipt failed to significantly alleviate apomorphine-induced rotation in unilateral 6-OHDA-lesioned PD model rats. However, using in vivo microdialysis in this PD model rats, it was found that Ipt could increase extracellular dopamine levels in the lesioned side of the striatum and decrease dopamine levels in the intact side of the striatum. Meanwhile, Ipt had no influence on glutamate levels in the intact side, but it did decrease glutamate levels in the lesioned side of the striatum of PD rats. Additionally, in primary cultured rat astrocytes, 6-OHDA decreased overall glutamate uptake activity, but this decrease was recovered and glutamate uptake activity was restored by the opening of KATP channels induced by Ipt and pinacidil. The classical KATP channel blocker glibenclamide completely abolished the effects of Ipt and pinacidil. The present study suggests that (i) the function of KATP channels in the lesioned and intact nigrostriatal pathway is different in unilateral 6-OHDA-lesioned PD model rats. (ii) KATP channels regulate extracellular neurotransmitter levels in the striatum of unilateral 6-OHDA-lesioned rats and may play neuroprotective roles due to their effects on glutamate transporters.

Topics: Adenosine Triphosphate; Animals; Antihypertensive Agents; Apomorphine; Astrocytes; Cells, Cultured; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Agonists; Extracellular Fluid; Glutamic Acid; Male; Microdialysis; Neurotransmitter Agents; Parkinsonian Disorders; Pinacidil; Potassium Channels, Inwardly Rectifying; Presynaptic Terminals; Propylamines; Rats; Rats, Sprague-Dawley; Synaptic Transmission

In a previous study, we demonstrated that iptakalim (Ipt) significantly ameliorated hypolocomotion and catalepsy induced by haloperidol and rotenone in rats. In order to further understand the mechanism(s), using a rat model of Parkinson's disease (PD) established by unilateral 6-hydroxydopamine (6-OHDA) administration to the substantia nigra pars compacta (SNpc) and reverse microdialysis techniques with high performance liquid chromatography (HPLC), we investigated the effects of Ipt on extracellular levels of glutamate, dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the striatum of conscious and freely moving rats. The results indicated that unilateral 6-OHDA-lesioned rats have a significantly higher level of extracellular glutamate and a lower level of extracellular DOPAC in the lesioned-side of the striatum, and a lower level of extracellular DA in both sides of the striatum compared to the striatum of control rats. Ipt reduced extracellular glutamate levels in both sides of striatum of the lesioned and control rats in a concentration-dependent manner. Ipt, at lower concentrations (0.01, 0.1, 1 microM), enhanced extracellular DA levels in the lesioned-side striatum of the unilateral 6-OHDA-lesioned rats, while causing no significant changes in the intact side striatum, and even a significant decline in striatum of control rats at higher concentrations of Ipt (10, 100 microM). In addition, Ipt also caused a significant decline in the extracellular DOPAC levels in the lesioned-side striatum of unilateral 6-OHDA-lesioned rats. These data suggest that the major mechanism underlying the ameliorative effects of Ipt on the behavior in 6-OHDA-lesioned rats is the alteration of levels of extracellular neurotransmitters, such as glutamate and DA in the striatum of unilateral 6-OHDA-lesioned rats.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Chromatography, High Pressure Liquid; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Extracellular Space; Glutamic Acid; Male; Microdialysis; Oxidopamine; Propylamines; Rats; Rats, Sprague-Dawley; Substantia Nigra

Our previous studies revealed that iptakalim, a novel ATP-sensitive potassium channel opener, has a significant neuroprotective function against ischemia in vivo or rotenone-induced neurotoxicity in vitro. To investigate the potential pharmaceutical benefit of ATP-sensitive potassium channel openers on neurodegenerative diseases, we studied the effects of iptakalim and diazoxide, a selective mitochondrial ATP-sensitive potassium channel opener, on the rotenone-induced nigrostriatal degeneration in rats. Iptakalim (1.5 mg/kg/day, orally) or diazoxide (1.5 mg/kg/day, orally) alone was administered to rats for 3 days, and then for 4 weeks was used daily with an injection of rotenone (2.5 mg/kg/day, subcutaneously) 1 hr later each time. The results showed that rotenone-infused rats exhibited parkinsonian symptoms and had dopamine depletion in the striatum and substantia nigra. Pretreatment with iptakalim or diazoxide prevented rotenone-induced catalepsy and the reduction of striatum dopamine contents. Moreover, iptakalim and diazoxide reduced the enzymatic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. These neuroprotective effects of iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium channel blocker. In conclusion, our data suggested that mitochondrial ATP-sensitive potassium channels might play a key role in preventing both parkinsonian symptoms and neurochemistry alterations induced by rotenone in rats. The selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for prevention and treatment of neurodegenerative disorders such as Parkinson's disease.

Topics: Adenosine Triphosphate; Animals; ATP-Binding Cassette Transporters; Basal Ganglia; Brain; Brain Chemistry; Catalepsy; Diazoxide; Disease Models, Animal; Dopamine; Down-Regulation; Drug Administration Schedule; Male; Nerve Tissue Proteins; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Parkinsonian Disorders; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotenone; Uncoupling Agents

Iptakalim hydrochloride (Ipt), a novel antihypertensive drug, exhibits K(ATP) channel activation. Here, we report that Ipt remarkably protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models. Chronic exposure of cultured PC12 cells to neurotoxins, such as 6-OHDA, MPP+, or rotenone, decreased overall [3H]-glutamate uptake in a concentration-dependent manner. Pre-treatment using 10 microM Ipt significantly protected cells against neurotoxin-induced glutamate uptake diminishment, and this protection was abolished by the K(ATP) channel blocker glibenclamide (20 microM), suggesting that the protective mechanisms may involve the opening of K(ATP) channels. In 6-OHDA-treated rats (as an in vivo Parkinson's disease model), [3H]-glutamate uptake was significantly lower in synaptosomes isolated from the striatum and cerebral cortex, but not the hippocampus. Pre-conditioning using 10, 50, and 100 microM Ipt significantly restored glutamate uptake impairment and these protections were abolished by blockade of K(ATP) channels. It is concluded that Ipt exhibits substantial protection of cells against neurotoxicity in in vitro and in vivo models. The cellular mechanisms of this protective effect may involve the opening of K(ATP) channels. Collectively, Ipt may serve as a novel and effective drug for PD therapy.

Topics: Amino Acid Transport System X-AG; Animals; Cerebral Cortex; Disease Models, Animal; Glutamic Acid; Male; Neostriatum; Neuroprotective Agents; Neurotoxins; Parkinsonian Disorders; PC12 Cells; Potassium Channels; Propylamines; Rats; Rats, Sprague-Dawley; Synaptosomes