Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain-derived neurotrophic factor (BDNF) deficiency has been implicated in pathogenesis of Huntington's disease (HD). 3-Nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, has been commonly used as a pharmacological model recapitulating HD phenotypes in rodents and nonhuman primates. Herein we test whether BDNF may exert neuroprotective effects against mitochondrial dysfunction caused by 3-NP in primary culture of fetal rat cortical neurons. Preconditioning of neuronal cells with BDNF (100 ng/ml for 8h) attenuated 3-NP toxicity (2.5 mM for additional 24h) based on Hoechst and propidium iodide (PI) staining. BDNF effects can be inhibited by the nitric oxide synthase (NOS) inhibitor L-nitroarginine methylester (L-NAME, 100 microM), the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (2 microM), the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB, 5 microM), and a membrane-permeable Bcl-2 inhibitor (12.5 microM). 8-Br-cGMP is a cGMP analogue capable of activating PKG independent of NO. Exogenous application of 8-Br-cGMP (3-30 microM) and purified thioredoxin (3-5 microM) partially mimicked BDNF effects in conferring 3-NP resistance to cortical cells. These results, together with our previous report showing NO donor S-nitrosoglutathione (GSNO)-mediated neuroprotective effects against 3-NP toxicity, suggest that BDNF may protect neurons from mitochondrial dysfunction at least partly via activation of the signaling cascades involving NOS/NO, PKG, thioredoxin and Bcl-2.
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PMID:Protective effects of brain-derived neurotrophic factor against neurotoxicity of 3-nitropropionic acid in rat cortical neurons. 1942 12

In this study, we determined whether minocycline may protect rat cortical cultures against neurotoxicity induced by sphingomyelinase/ceramide and explored the underlying mechanisms. We found that minocycline exerted strong neuroprotective effects against toxicity induced by bacterial sphingomyelinase and synthetic C2 ceramide. Minocycline enhanced the production of nitric oxide (NO) with resultant increases in cellular cGMP content. Consistently, minocycline-dependent neuroprotection was abolished by the nitric oxide synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) and the soluble guanylate cyclase (sGC) inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). Western blotting revealed that minocycline restored the expression levels of cGMP-dependent protein kinase (PKG)-1, antioxidative thioredoxin-1, and antiapoptotic Bcl-2 that were down-regulated by bacterial sphingomyelinase. Accordingly, the PKG inhibitor KT5823, the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), and a Bcl-2 inhibitor significantly abolished the minocycline neuroprotection. The minocycline-dependent restoration of Bcl-2 was abolished by L-NAME, ODQ, and KT5823, but not by DNCB, suggesting the involvement of NO/sGC/PKG but not thioredoxin. Furthermore, minocycline-dependent recovery of thioredoxin-1 was PKG-independent. Taken together, our results indicate that minocycline protects rat cortical neurons against bacterial sphingomyelinase/ceramide toxicity via an NO/cGMP/PKG pathway with induction of Bcl-2 and PKG-independent stimulation of thioredoxin-1.
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PMID:Neuroprotective mechanisms of minocycline against sphingomyelinase/ceramide toxicity: Roles of Bcl-2 and thioredoxin. 2118 25