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Obesity exacerbates chemically induced neurodegeneration
K Sriram1, S A Benkovic, D B Miller
1HELD/TMBB, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Mailstop L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA.
Neuroscience
|November 28, 2002
Summary
Obesity exacerbates neurotoxicity from methamphetamine and kainic acid in mice, increasing mortality and brain damage. This suggests obesity is a risk factor for neurodegeneration, potentially due to mitochondrial dysfunction.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Toxicology
Background:
- Obesity is a known risk factor for various systemic disorders.
- The impact of obesity on the nervous system and neurotoxicity is not well understood.
- Investigating obesity's role in neurodegeneration is crucial for public health.
Purpose of the Study:
- To determine if obesity acts as a risk factor for neurotoxicity.
- To evaluate the effect of obesity on the neurotoxic outcomes of methamphetamine (METH) and kainic acid (KA) exposure.
- To explore the underlying mechanisms of enhanced neurotoxicity in obesity.
Main Methods:
- Utilized ob/ob mice, an animal model of obesity, and their lean littermates.
- Administered neurotoxicants methamphetamine (METH) and kainic acid (KA) to assess neurotoxicity.
- Measured neurodegeneration markers, including dopamine levels, tyrosine hydroxylase, glial fibrillary acidic protein, Fluoro-Jade B staining, and microtubule-associated protein-2 immunoreactivity.
- Assessed mitochondrial uncoupling protein-2 (UCP-2) expression and its relation to ATP yield and oxidative stress.
Main Results:
- Obese ob/ob mice exhibited increased mortality following METH and KA administration compared to lean mice.
- METH exposure caused significantly exacerbated dopaminergic neurodegeneration and reactive gliosis in obese mice.
- KA treatment led to increased hippocampal neurodegeneration and reactive gliosis in obese mice, even at non-toxic doses for lean mice.
- Obese mice showed greater upregulation of mitochondrial uncoupling protein-2, suggesting impaired mitochondrial function and increased oxidative stress.
Conclusions:
- Obesity significantly enhances susceptibility to neurotoxicity induced by METH and KA.
- These findings implicate obesity as a critical risk factor for chemical-induced neurodegeneration.
- The observed mitochondrial dysfunction in obese mice may underlie the heightened neurotoxic vulnerability.