Effects of sleep modulation on stroke recovery in rats

Abstract

The general aim of the present thesis was to investigate the role of sleep in the recovery process of the brain after ischemic stroke in rats, and in particular to understand whether sleep promotion could improve post-stroke recovery. Sleep-wake disturbances have been described in patients suffering from stroke and appear to have a negative impact on rehabilitation and long-term outcomes. In the experimental stroke model, sleep disruption has detrimental effects on infarct size, expression of plasticity-related genes, and functional recovery, while sleep stimulant gamma-hydroxybutyrate (GHB) accelerates stroke recovery in mice. Yet, the role of sleep and its underlying mechanisms in modulating the injured brain and clinical outcomes are poorly known. Promotion of neuroplasticity during recovery may represent an effective therapeutic strategy and, since sleep has been implicated in facilitation of neuroplasticity, approaches targeting sleep may lead to development of treatment able to improve long- term functional outcome after stroke. The first goal was to evaluate whether two pharmacological agents, baclofen (Bac) and GHB would induce a physiological sleep in rats. Recently, a lot of effort have been put to create drugs acting through GABA receptors in order to promote physiological sleep for therapeutic purposes. Both drugs, which act through GABAB receptors, have been shown to promote sleep in humans, but their effects in rodents remain unclear. The results of this study demonstrated that Bac and GHB induced a non-physiological state characterised by atypical behaviour and abnormal electroencephalogram (EEG) pattern, and affected vigilance in rats. However, the principal finding was that Bac, but not GHB, had sleep- promoting properties (facilitated and consolidated sleep). Therefore, as the next step we decided to use Bac as a sleep-promoting drug and evaluate effects on functional recovery after stroke. The second study aimed at investigating stroke outcome following repeated treatment with Bac in a rat model of focal cerebral ischemia. The first injections of Bac or saline were given 24 h after initiation of ischemia and then twice daily for 10 consecutive days. The data demonstrated that repeated Bac treatment after stroke affected sleep, neuroplasticity and motor function but not the size of the brain damage. Thus, Bac administration increased non-rapid eye movement (NREM) sleep amount and improved motor function recovery concomitantly with enhanced axonal sprouting and neurogenesis. Furthermore, although Bac had no effect on the size of the lesion volume, it reduced atrophy of the corpus callosum. These results indicate that delayed repeated Bac treatment promotes neuronal plasticity after stroke and thereby benefits motor function recovery. We suggest that observed effects might be mediated by sleep, emphasizing the importance of sleep in recovery processes. In summary, the results of this work contribute to the understanding of the sleep- modulating effects on stroke recovery processes, indicating that pharmacological sleep promotion could mediate and enhance endogenous recovery mechanisms in a rat model of focal cerebral ischemia. Furthermore, these studies not only advance our knowledge in basic principles of sleep function in the injured brain but may also offer a rationale for a novel strategy to promote recovery after stroke, and possibly other brain injuries, by developing sleep-modulating treatments