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Resistance to 3-mercaptopropionic acid-induced seizures in hepatic encephalopathy
M R Ferreira1, S H Gammal, E A Jones
1Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Background/Aims:
To determine if a model of hepatic encephalopathy (HE) exhibits decreased sensitivity to the neuronal effects of a drug that induces seizures as a consequence of decreasing GABA-mediated inhibitory neurotransmission.
Materials And Methods:
3-Mercaptopropionic Acid (MPA) is an inhibitor of L-glutamate decarboxylase which catalyzes the synthesis of GABA from glutamate. MPA was administered, either by intraperitoneal or intracerebroventricular injection, into rats with stage III HE due to thioacetamide-induced fulminant hepatic failure and into normal control rats.
Results:
When MPA was administered by intraperitoneal injection, seizure-inducing doses were similar for rats with HE and control rats. However, when a constant dose of MPA (330 micrograms) was administered by intracerebroventricular injection, rats with HE took significantly longer to develop seizures than control rats (16.2 vs. 7.3 minutes; p < 0.0005).
Conclusions:
In a model of HE: (i) There is increased resistance to the convulsive effects of MPA; and (ii) This phenomenon is apparent when MPA is given centrally, but not when it is given peripherally. Increased resistance to the development of a complication of reduced GABA-mediated neurotransmission induced by MPA in the model provides support for the hypothesis that HE is associated with increased GABA-mediated inhibitory neurotransmission.
Insights
Hepatic encephalopathy (HE) models show reduced seizure susceptibility to GABA-reducing drugs when administered centrally. This suggests HE may involve increased inhibitory neurotransmission, impacting neuronal function.
Area of Science:
- Neuroscience
- Gastroenterology
- Pharmacology
Background:
- Hepatic encephalopathy (HE) is a complex neurological complication of liver failure.
- HE is associated with altered neurotransmission, particularly involving gamma-aminobutyric acid (GABA).
Purpose of the Study:
- To investigate the neuronal sensitivity to GABAergic drugs in a rat model of HE.
- To determine if HE alters seizure threshold in response to GABA synthesis inhibition.
Main Methods:
- Rats with thioacetamide-induced HE and control rats received 3-Mercaptopropionic Acid (MPA), a GABA synthesis inhibitor.
- MPA was administered via intraperitoneal or intracerebroventricular injection.
- Seizure latency was recorded after MPA administration.
Main Results:
- Peripheral MPA administration resulted in similar seizure thresholds in HE and control rats.
- Central (intracerebroventricular) MPA administration led to significantly longer seizure latency in HE rats compared to controls (16.2 vs. 7.3 minutes).
Conclusions:
- A rat model of HE exhibits increased resistance to the pro-convulsant effects of MPA.
- This resistance is observed with central MPA administration, suggesting altered central nervous system sensitivity.
- Findings support the hypothesis that HE is associated with enhanced GABA-mediated inhibitory neurotransmission.