Abstract
The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1 µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5–10 µM) on locomotor networks in-vitro. Nicotine 10 µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5–1 µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes indicating a stress response. Excitotoxicity induced by kainate was contrasted by nicotine (10 µM) in the dorsal area and persisted in central and ventral regions with no change in basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine.
Highlights
Transient application of nicotine (Nic) to brain and spinal motor networks in vitro can robustly protect them from excitotoxicity and neurodegeneration [1–3]
The application of 0.5 and 1 μM nicotine for 4 h exhibited a neuroprotective effect on such neurons in the ventral horn as their number was higher than in sham preparations 24 later, suggesting that this drug had likely slowed down the standard neuronal loss usually occurring during long in vitro maintenance
Substantial data are available on nicotinic acetylcholine receptors (nAChRs) as a potential target to rescue from neurodegeneration using nicotine [1–3]
Summary
Transient application of nicotine (Nic) to brain and spinal motor networks in vitro can robustly protect them from excitotoxicity and neurodegeneration [1–3]. Using the isolated rodent spinal cord maintained in vitro for 24 h as a model of acute spinal injury [4,5], we have observed that nicotine evokes a neuroprotective action against excitotoxic damage induced by the glutamate agonist kainate; KA [2]. Acute administration of nicotine to smokers with spinal cord injury (SCI) induces a sharp increase in neuropathic pain [6], demonstrating a dual action of nicotine. In a spinal cord model, we set out to investigate the borderline between neuroprotection and toxicity exerted by nicotine to discover mechanisms that could contrast this transition. The neurotoxicity of nicotine is widely documented [10], especially in young people [11], little is known about its possible toxic effects on spinal networks. High-dose nicotine is a well-known convulsive agent that activates brain centers [12,13], whether nicotine can cause hyperexcitability or depression of spinal circuitries is unclear
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