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Uncoupling of cerebral glucose supply and utilization after hexane-2,5-dione intoxication in the rat
Abstract:
Chronic administration of hexane-2,5-dione (2,5-HD) to rats causes an accumulation of neurofilaments within axons that may lead to their degeneration. This occurs in both the CNS and PNS. It has been suggested that one of the effects of 2,5-HD is an impairment of glucose utilization arising from an inhibition of specific glycolytic enzymes. This hypothesis is based principally on evidence obtained in vitro. In the present study, glucose utilization, glucose transport across the blood-brain barrier, and blood flow have been measured in vivo in brain regions of control rats and in three groups of rats treated with 2,5-HD as (a) a single intragastric dose (500 mg/kg of body weight), (b) high chronic doses of 500 mg/kg of body weight for 15 days, or (c) low chronic doses of 250 mg/kg of body weight for 21 days. Group b showed overt signs of neuropathy, whereas groups a and c did not. The results indicate two independent effects of 2,5-HD in the CNS: a dose-dependent inhibition of glucose utilization and an effect on glucose supply and transport across the blood-brain barrier, which is apparent only after chronic treatment.
Insights
Hexane-2,5-dione (2,5-HD) causes neurofilament accumulation and axonal degeneration. In vivo studies reveal 2,5-HD dose-dependently inhibits glucose utilization and chronically impairs blood-brain barrier glucose transport.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Hexane-2,5-dione (2,5-HD) induces neurofilament accumulation and axonal degeneration in the central and peripheral nervous systems.
- In vitro studies suggest 2,5-HD impairs glucose utilization by inhibiting glycolytic enzymes.
Purpose of the Study:
- To investigate the in vivo effects of 2,5-HD on glucose utilization, blood-brain barrier transport, and blood flow in rat brains.
- To determine if 2,5-HD's effects on glucose metabolism are dose-dependent and manifest after acute or chronic administration.
Main Methods:
- Rats were administered single or chronic doses of 2,5-HD (500 mg/kg or 250 mg/kg).
- In vivo measurements of glucose utilization, glucose transport across the blood-brain barrier, and regional cerebral blood flow were performed.
- Neuropathic signs were assessed in treated rats.
Main Results:
- Chronic high-dose 2,5-HD (500 mg/kg for 15 days) induced overt neuropathy.
- A dose-dependent inhibition of glucose utilization in the CNS was observed.
- Impairment of glucose supply and transport across the blood-brain barrier was evident only after chronic 2,5-HD treatment.
Conclusions:
- 2,5-HD exerts at least two independent effects on the CNS: direct inhibition of glucose utilization and chronic disruption of glucose transport across the blood-brain barrier.
- These findings provide in vivo evidence supporting the hypothesis that impaired glucose metabolism contributes to 2,5-HD neurotoxicity.
