Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice

Get those human clinical trials going. Trillions of neurons need saving everyday we waste.  Call the ASA, NSA and WSO and ask what they are doing to save neurons.

http://www.sciencedirect.com/science/article/pii/S0028390812005461

Abstract

Traumatic brain injury (TBI) evokes an intense neuroinflammatory reaction that is essentially mediated by activated microglia and that has been reported to act as a secondary injury mechanism that further promotes neuronal death. It involves the excessive production of inflammatory cytokines and the diminution of neuroprotective and neurotrophic factors, such as the soluble form alpha of the amyloid precursor protein (sAPPα), generated by the activity of α-secretases. Hence, the aim of this study was to examine the effects of etazolate, an α-secretase activator, on acute and belated post-TBI consequences. The mouse model of TBI by mechanical percussion was used and injured mice received either the vehicle or etazolate at the dose of 1, 3 or 10 mg/kg at 2 h post-TBI. Neurological score, cerebral œdema, IL-1β and sAPPα levels, microglial activation and lesion size were evaluated from 6 to 24 h post-TBI. Spontaneous locomotor activity was evaluated from 48 h to 12 weeks post-TBI, memory function at 5 weeks and olfactory bulb lesions at 13 weeks post-TBI. A single administration of etazolate exerted a dose-dependent anti-inflammatory and anti-œdematous effect accompanied by lasting memory improvement, reduction of locomotor hyperactivity and olfactory bulb tissue protection, with a therapeutic window of at least 2 h. These effects were associated with the restoration of the levels of the sAPPα protein post-TBI. Taken together, these results highlight for the first time the therapeutic interest of an α-secretase activator in TBI.

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Highlights

► The post-TBI levels of sAPPα were restored by etazolate treatment. ► Etazolate decreases IL-1β levels, cerebral oedema and microglial activation. ► Locomotor hyperactivity and memory deficit were attenuated by etazolate treatment. ► Etazolate protects olfactory bulb tissue in a persistent manner. ► The therapeutic window of etazolate is at least 2 h.