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  • The molecular identity of RA

    2021-11-29

    The molecular identity of RA’s target Jurassic Park during LTP induction was determined by pharmacological testing. The inhibitory effects of CNQX and niflumic acid on LTP induction remained even in the presence of RA, indicating RA did not affect either the AMPA receptor nor chloride channel (Fig. 2B and D) [26], [27]. However, AP-5 interference of LTP induction was reversed by RA, signifying its role on the NMDA receptor (Fig. 1D) [28]. This finding suggests that LTP induction by RA is attributable to NMDA receptor activation. Recent studies have reported that incubation of rodent hippocampal slices with small diffusible amyloid beta (Aβ) oligomers strongly inhibits LTP induction [29], [30]. If RA prevents amyloid beta oligomer from disrupting LTP, it might be a candidate for memory loss prevention in Alzheimer’s disease. Scopolamine is a muscarinic Jurassic Park receptor blocker and is used to induce memory impairment in animal models [23]. Scopolamine decreased LTP in the present study, but the level of LTP was recovered in the RA-treated group (Fig. 3B). These results highlight several novel aspects of this study. First, we demonstrated the neuroprotective effect of RA in a scopolamine model. In terms of cognitive impairment, cellular toxicity was also examined after longer time points of 24 h and 48 h. RA prevention from scopolamine-induced neuronal cell death was confirmed by PI staining (Fig. 4). Therefore, RA not only induces LTP, but also evokes neuroprotective effects in a scopolamine-induced memory impairment model.
    Conflicts of interest
    The crucial significance of white matter injury in stroke Stroke arises from a focal loss of vascular supply to the brain. According to the World Health Organization for data from 2016, it is the second most common cause of premature death in the world after ischemic heart disease and is responsible for almost six million fatalities annually. White matter (WM) involvement in stroke has been recognized since the extent of focal lesions called lacunar infarcts were highlighted by the pioneering work of C. M. Fisher1. Lacunar infarcts represent ∼20% of all stroke and are frequently restricted to WM. In addition to these “pure” WM stroke injuries, larger cortical strokes also incorporate regions of subcortical WM and it has been estimated that ∼95% of clinical strokes involve WM injury, which accounts for ∼49% of stroke total mean infarct volume [115]. Since WM houses essential axonal projections, loss of WM function in stroke is as significant for brain function as loss of the neuronal somata and synapses in the grey matter (GM). Due to the relatively small amount of WM in experimental rodent models, we have recently argued that WM is far more significant to neurological disease including stroke than has generally been appreciated [33]. In humans, WM occupies ∼50% of brain volume and is composed of myelinated and non-myelinated axons, supporting glial cells (astrocytes, oligodendrocytes, microglia) and vasculature. Unlike the complex signal integration and memory formation mechanisms performed in GM, WM has only one simple function: action potential conduction. WM stroke injury will affect CNS function only if it compromises action potential conduction in axons. Rapid myelin damage is a feature of WM stroke injury [77] and remyelination failure in WM lesions results in significantly functional loss [52,100]. The mechanisms underlying myelin injury in acute ischemic lesions clearly have high clinical relevance and may share common features with other forms of myelin damage, for example those operating in multiple sclerosis and CNS trauma [70,85]. In grey matter (GM), the principal mechanism of acute ischemic injury is excitotoxicity involving glutamate release, glutamate receptor (GluR) activation, cytotoxic Ca2+ elevation and further glutamate release. There is growing evidence that the principle mechanisms of myelin damage in stroke are also a form of excitotoxic injury mediated by myelinic GluR over-activation. In addition to myelin, WM GluRs are expressed on the oligodendrocyte cell bodies responsible for generating and maintaining myelin, and these cell bodies are also highly susceptible to excitotoxic ischemic injury. While myelin and oligodendrocyte pathophysiology has been a focus of interest in WM stroke, axonal function will also be compromised by direct injury to the axon cylinder itself, or by failure of the homeostatic functions performed by astrocytes. The significance of WM GluR expression for WM stroke injury is the focus of this review and we will examine the role of GluRs in injury to myelin, oligodendrocytes, astrocytes and the axon cylinder.