Nicotinic receptors modulate the onset of reactive oxygen species production and mitochondrial dysfunction evoked by glutamate uptake block in the rat hypoglossal nucleus
In several neurodegenerative diseases, glutamate-mediated excitotoxicity is considered to be a major process to initiate cell degeneration. Indeed, subsequent to excessive glutamate receptor stimulation, reactive oxygen species (ROS) generation and mitochondrial dysfunction are regarded as two major gateways leading to neuron death. These processes are mimicked in an in vitro model of rat brainstem slice when excitotoxicity is induced by DL-threo-β-benzyloxyaspartate (TBOA), a specific glutamate-uptake blocker that increases extracellular glutamate. Our recent study has demonstrated that brainstem hypoglossal motoneurons, which are very vulnerable to this damage, were neuroprotected from excitotoxicity with nicotine application through the activation of nicotinic acetylcholine receptors (nAChRs) and subsequent inhibition of ROS and mitochondrial dysfunction. The present study examined if endogenous cholinergic activity exerted any protective effect in this pathophysiological model and how ROS production (estimated with rhodamine fluorescence) and mitochondrial dysfunction (measured as methyltetrazolium reduction) were time-related during the early phase of excitotoxicity (0-4h). nAChR antagonists did not modify TBOA-evoked ROS production (that was nearly doubled over control) or mitochondrial impairment (25% decline), suggesting that intrinsic nAChR activity was insufficient to contrast excitotoxicity and needed further stimulation with nicotine to become effective. ROS production always preceded mitochondrial dysfunction by about 2h. Nicotine prevented both ROS production and mitochondrial metabolic depression with a delayed action that alluded to a complex chain of events targeting these two lesional processes. The present data indicate a relatively wide time frame during which strong nAChR activation can arrest a runaway neurotoxic process leading to cell death.
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