A network map of GDNF/RET signaling pathway in physiological and pathological conditions.

Glial cell line-derived neurotrophic factor (GDNF) signals through a multi-component receptor system predominantly consisting of glycosyl-phosphatidylinositol-anchored GDNF family receptor alpha-1 (GFRα1) and the Rearranged during transfection (RET) receptor tyrosine kinase. GDNF/RET signaling is vital to the central and peripheral nervous system, kidney morphogenesis, and spermatogenesis. In addition, the dysregulation of the GDNF/RET signaling has been implicated in the pathogenesis of cancers. Despite the extensive research on GDNF/RET signaling, a molecular network of reactions induced by GDNF reported across the published literature. However, a comprehensive GDNF/RET pathway resource is currently unavailable. We describe an integrated signaling pathway reaction map of GDNF/RET consisting of 1151 molecular reactions. These include information pertaining to 52 molecular association events, 70 enzyme catalysis events, 36 activation/inhibition events, 22 translocation events, 856 gene regulation events, and 115 protein-level expression events induced by GDNF in diverse cell types. We developed a comprehensive GDNF/RET signaling network map based on these molecular reactions. The pathway map was made accessible through WikiPathways database ( https://www.wikipathways.org/index.php/Pathway:WP5143 ). Biocuration and development of gene regulatory network map of GDNF/RET signaling pathway.

Efonidipine-Induced Exanthematic Drug Eruption and Literature Review.

We report the case of an elderly woman who developed exanthematic drug eruption after administration of efonidipine. An 84-year-old woman presented to emergency department with complaints of generalized itching and erythema since 4 days. She was on human-soluble insulin since 11 years. In view of her hypertension and left anterior descending artery stenosis, she was initiated on aspirin, clopidogrel, atorvastatin, pantoprazole, nebivolol, aldactone, and efonidipine a week ago. Her presenting complaints were initially managed with parenteral pheniramine maleate and hydrocortisone. She was admitted, and all her medications except antiplatelets and insulin were discontinued. She was prescribed topical beclomethasone and oral antihistamines for better control of her symptoms. To confirm the drug precipitating the reaction, she was rechallenged with efonidipine, 20 mg once daily on the third day of admission. She developed itching 8 hours after administering the medication, and efonidipine was stopped and nebivolol 5 mg once daily was restarted for hypertension. She did not develop any adverse event when the remaining medications were reinitiated. World Health Organization-Uppsala Monitoring Centre causality assessment criteria indicated a "certain" association. To the best of the knowledge of the authors, this is one among the first reported cases of efonidipine-induced exanthematic drug eruption.

Nimodipine attenuates the parkinsonian neurotoxin, MPTP-induced changes in the calcium binding proteins, calpain and calbindin.

We have recently demonstrated neuroprotective abilities of nimodipine, an L-type voltage dependent calcium channel (VDCC) blocker in cellular and animal models of Parkinson's disease (PD). To understand the calcium regulatory mechanisms in the disease pathogenesis, the present study examined calcium regulatory proteins calbindin and calpain mRNA and protein levels employing quantitative PCR and western blot in 1-methyl-4-phenyl pyridinium ion (MPP+)-treated SH-SY5Y cell lines and in the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). mRNA and protein levels of calbindin were lower, while that of calpain were higher in MPP+-treated SH-SY5Y cells and MPTP-treated mouse striatum as compared to their respective controls. Nimodipine pretreatment significantly attenuated these effects in the parkinsonian neurotoxin-treated SH-SY5Y cell line and in the mouse striatum. The activities of the apoptotic mediator, caspase-3 and calpain were increased in the neurotoxin-treated groups as compared to their respective controls, which was ameliorated by nimodipine pretreatment. These results suggest that parkinsonian neurotoxin-mediated dopaminergic neuronal death might involve defects in calcium regulatory proteins that control intracellular calcium homeostasis, and these could be corrected by inhibiting L-type VDCC activity. These findings support the notion that hypertensive patients who are on long-term intake of dihydropyridine have reduced risk for PD.

1-Methyl-4-Phenylpyridinium-Induced Death of Differentiated SH-SY5Y Neurons Is Potentiated by Cholesterol.

BACKGROUND/AIMS: Hypercholesterolemia is recently considered a risk factor for Parkinson's disease (PD), the most consistent neurodegenerative movement disorder. The study aimed to investigate the effect of exogenous cholesterol on 1-methyl-4-phenylpyridinium (MPP+) parkinsonian neurotoxin-induced cell death, loss of mitochondrial membrane potential, and dopaminergic deficiency in a cellular model of PD. METHODS: Cholesterol (50 µM) when added in the culture media alone or in combination with MPP+ was studied in SH-SY5Y neuroblastoma cells. There were 4 groups that were studied; SH-SY5Y cells treated with vehicle (control), cells that were treated with 1 mM MPP+ (MPP+), or cholesterol (chol) or both (M + chol). The loss of cell survival was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Dopamine depletion, microtubule-associated protein 2 (MAP-2), and tyrosine hydroxylase (TH)-positive neuronal loss were determined by HPLC-electrochemical detection and TH immunocytochemistry respectively. Mitochondrial membrane potential in cells stained by tetramethylrhodamine methyl ester dye was analysed by flow cytometry. RESULTS: Cholesterol treatment potentiated a reduction of neuronal viability with loss of TH-positive neurons in cultures. MPP+-induced depletion of dopamine level in the post-mitotic MAP-2 immunoreactive neurons and loss of mitochondrial membrane potential were also heightened by cholesterol. CONCLUSION: Apparently, changes in neuronal cholesterol content significantly influenced the neurotoxicity and the direct mitochondrial mechanisms involved in MPP+-induced cell death. Our observations demonstrate that high cholesterol incorporated into the differentiated human neuroblastoma cells worsened dopaminergic neuronal survivability through increased depolarization of mitochondrial membrane potential, which is a known mechanism of dopaminergic cell death by MPP+. The present findings support the hypothesis that hypercholesterolemia could be a risk factor for PD.