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The amine-depleting effects of 5,7-dihydroxytryptamine (5,7-DHT) in C57BL/6 mice do not increase with age
K T Finnegan1, L E DeLanney, I Irwin
1Institute for Medical Research, San Jose, CA 95128.
Abstract:
A recent approach to identifying the factors that predispose neurons to an early death in Parkinson's or Alzheimer's disease has been to study how the effect of specific neurotoxins are altered by increasing maturity. We determined the dose-related serotonin and norepinephrine-depleting effects of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), in C57BL/6 mice of 2 different ages. Norepinephrine and serotonin in the hippocampus were assayed 1 week after the intracerebroventricular (i.c.v.) administration of 5,7-DHT. 5,7-DHT produced an equivalent, dose-related depletion of hippocampal norepinephrine in both age groups. Since the effects of 5,7-DHT on noradrenergic neurons may, at least in part, depend on the monoamine oxidase (MAO)-generated formation of hydrogen peroxide and associated oxy-radicals, this result suggests that noradrenergic neurons do not become more vulnerable to oxidative stress with aging. We also found that the noradrenergic-depleting effects of 5,7-DHT were blocked by the non-selective MAO inhibitor pargyline (50 mg/kg, i.p.), while the selective MAO B inhibitor deprenyl (10 mg/kg, i.p.) failed to prevent this depletion. These latter results suggest that it is the A form of MAO that plays an important role in the mechanism of 5,7-DHT-induced noradrenergic toxicity. Somewhat unexpectedly, older mice were found to be less susceptible to the serotonin-depleting effects of 5,7-DHT. Although the mechanism by which this compound damages serotonergic neurons is uncertain, our results show that the increased susceptibility of serotonergic neurons to 5,7-DHT in young animals extends well beyond the neonatal period.
Insights
Aging does not increase vulnerability of noradrenergic neurons to oxidative stress from 5,7-dihydroxytryptamine (5,7-DHT). Older mice showed reduced susceptibility to 5,7-DHT
Area of Science:
- Neuroscience
- Toxicology
- Aging Research
Background:
- Neurodegenerative diseases like Parkinson's and Alzheimer's involve neuronal death.
- Understanding neurotoxin effects across different ages is crucial for identifying disease predispositions.
- Maturity can alter the impact of neurotoxins on neuronal vulnerability.
Purpose of the Study:
- To investigate the age-related effects of 5,7-dihydroxytryptamine (5,7-DHT) on serotonin and norepinephrine depletion in mouse hippocampus.
- To determine the role of monoamine oxidase (MAO) in 5,7-DHT-induced neurotoxicity.
- To assess if noradrenergic neurons become more vulnerable to oxidative stress with aging.
Main Methods:
- Administered varying doses of 5,7-DHT intracerebroventricularly (i.c.v.) to C57BL/6 mice of two different ages.
- Assayed hippocampal norepinephrine and serotonin levels one week post-administration.
- Utilized MAO inhibitors (pargyline and deprenyl) to explore the mechanism of 5,7-DHT toxicity.
Main Results:
- 5,7-DHT caused a dose-related depletion of hippocampal norepinephrine in both young and old mice, indicating no increased vulnerability with age.
- The noradrenergic-depleting effects of 5,7-DHT were blocked by the MAO A inhibitor pargyline but not by the MAO B inhibitor deprenyl.
- Older mice exhibited reduced susceptibility to the serotonin-depleting effects of 5,7-DHT compared to younger mice.
Conclusions:
- Noradrenergic neurons do not appear to become more vulnerable to oxidative stress-related damage from 5,7-DHT with aging.
- Monoamine oxidase A (MAO A) plays a significant role in the neurotoxic mechanism of 5,7-DHT on noradrenergic neurons.
- Increased susceptibility of serotonergic neurons to 5,7-DHT is not limited to the neonatal period and persists in young adulthood.