Related Experiment Videos
Inhibition of nitric oxide synthase activity attenuates striatal malonate lesions in rats
1Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109-0646, USA.
Abstract:
Mitochondrial inhibitors such as malonate are potent neurotoxins in vivo. Intrastriatal injections of malonate result in neuronal damage reminiscent of "excitotoxic" lesions produced by compounds that activate NMDA receptors. Although the mechanism of cell death produced by malonate is uncertain, overactivation of NMDA receptors may be involved; pretreatment of animals with NMDA antagonists provides neuroprotection against malonate lesions. NMDA receptor activation stimulates the enzyme nitric oxide (NO) synthase (NOS). Elevated tissue levels of NO may generate highly reactive intermediates that impair mitochondrial function. We hypothesized that NO may be a mediator of malonate toxicity. We investigated whether in vivo inhibition of NO production by the NOS inhibitor N omega-nitro-L-arginine (NLA) would attenuate lesions produced by intrastriatal injections of malonate. We found that systemic injections of 3 mg/kg of NLA significantly reduced the extent of histologic damage elicited by intrastriatal injections of 1.5 mumol of malonate in adult rats.
Insights
Mitochondrial toxins like malonate cause neurotoxicity. Inhibiting nitric oxide (NO) production with N omega-nitro-L-arginine (NLA) protected against malonate-induced brain damage in rats.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Mitochondrial inhibitors, such as malonate, are potent neurotoxins.
- Malonate-induced neuronal damage resembles excitotoxic lesions, suggesting a role for NMDA receptors.
- NMDA receptor activation increases nitric oxide (NO) production, which may impair mitochondrial function.
Purpose of the Study:
- To investigate if NO mediates malonate toxicity.
- To determine if inhibiting NO production attenuates malonate-induced neurotoxicity.
Main Methods:
- Intrastriatal malonate injections were used to induce neuronal damage in adult rats.
- Systemic administration of N omega-nitro-L-arginine (NLA), a nitric oxide synthase (NOS) inhibitor, was employed.
- Histologic damage was assessed to evaluate the neuroprotective effects of NLA.
Main Results:
- Malonate injections caused significant neuronal damage in the striatum.
- Systemic pretreatment with NLA (3 mg/kg) significantly reduced the extent of malonate-induced histologic damage.
- This suggests that NO plays a role in malonate neurotoxicity.
Conclusions:
- Nitric oxide (NO) is implicated as a mediator of malonate neurotoxicity.
- Inhibiting NO production with NLA offers neuroprotection against malonate-induced brain lesions.
- These findings highlight a potential therapeutic target for mitigating neurotoxin-induced damage.