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A protein kinase C inhibitor attenuates cyanide toxicity in vivo
E U Maduh1, E W Nealley, H Song
1Pharmacology Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Abstract:
We have examined the effect of pretreatment with a potent protein kinase C (PKC) inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), against metabolic alterations induced by sodium cyanide (NaCN), 4.2 mg/kg, in brain of anesthetized male micropigs (6-10 kg). Brain high energy phosphates were analyzed using a 31P nuclear magnetic resonance (NMR) spectroscopic surface coil in a 4.7 Telsa horizontal bore magnet. H-7, 1 mg/kg, was given intravenously (i.v.) 30 min before NaCN challenge (H-7 + CN-). Prior to NaCN, H-7, or H-7 + CN- administration, baseline 31P resonance spectra of 1-min duration were acquired for 5-10 min, and continued for an additional 60 min following i.v. NaCN injection, each animal serving as its own control. Peaks were identified as phosphomonoester (PME), inorganic phosphate (Pi), phosphodiester (PDE), phosphocreatine (PCr) and adenosine triphosphate (ATP), based on their respective chemical shifts. Without H-7 pretreatment, NaCN effects were marked by a rising Pi and a declining PCr peak 2 min after injection, with only 2/5 of the animals surviving the 60 min experiment. Through a pretreatment period of 30 min, H-7 did not affect baseline cell energy profile as reflected by the 31P-NMR spectra, but in its presence, those changes (i.e. diminishing PCr and rising Pi peaks) elicited by NaCN were markedly blunted; 4/5 of the animals in this group survived the NaCN challenge. It is proposed that H-7, a pharmacologic inhibitor of PKC, may be useful in CN- antagonism, underscoring the role of PKC in cyanide intoxication.
Insights
Protein kinase C (PKC) inhibitor H-7 protected micropig brains from cyanide-induced metabolic damage. Pretreatment with H-7 blunted harmful changes in brain energy phosphates and improved survival rates following sodium cyanide exposure.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Cyanide intoxication causes severe metabolic disturbances in the brain.
- Protein kinase C (PKC) is implicated in cellular responses to toxins.
- Understanding protective mechanisms against cyanide is crucial for developing effective antidotes.
Purpose of the Study:
- To investigate the neuroprotective effects of a protein kinase C (PKC) inhibitor, H-7, against sodium cyanide (NaCN)-induced metabolic alterations in the brain.
- To assess the impact of H-7 pretreatment on brain high-energy phosphate levels and survival rates in a micropig model of cyanide poisoning.
Main Methods:
- Anesthetized male micropigs were used to study the effects of NaCN (4.2 mg/kg).
- 31P nuclear magnetic resonance (NMR) spectroscopy was employed to analyze brain high-energy phosphates (ATP, PCr, Pi, PME, PDE).
- Animals were pretreated with H-7 (1 mg/kg, i.v.) 30 minutes prior to NaCN challenge, with each animal serving as its own control.
Main Results:
- NaCN administration without H-7 pretreatment led to a rapid decline in phosphocreatine (PCr) and a rise in inorganic phosphate (Pi), with low survival rates (2/5).
- H-7 pretreatment did not alter baseline brain energy profiles but significantly blunted the NaCN-induced changes in PCr and Pi.
- Survival rates improved to 4/5 in the H-7 pretreated group, indicating a protective effect against cyanide toxicity.
Conclusions:
- H-7, a potent inhibitor of PKC, demonstrates significant neuroprotective effects against cyanide-induced metabolic disruption in the brain.
- These findings suggest that PKC plays a critical role in the pathophysiology of cyanide intoxication.
- PKC inhibition may represent a viable therapeutic strategy for managing cyanide poisoning.