Abstract
Traumatic brain injury (TBI) is a widespread cause of death and a major source of adult disability. Subsequent pathological events occurring in the brain after TBI, referred to as secondary injury, continue to damage surrounding tissue resulting in substantial neuronal loss. One of the hallmarks of the secondary injury process is microglial activation resulting in increased cytokine production. Notwithstanding that recent studies demonstrated that caloric restriction (CR) lasting several months prior to an acute TBI exhibits neuroprotective properties, understanding how exactly CR influences secondary injury is still unclear. The goal of the present study was to examine whether CR (50% of daily food intake for 3 months) alleviates the effects of secondary injury on neuronal loss following cortical stab injury (CSI). To this end, we examined the effects of CR on the microglial activation, tumor necrosis factor-α (TNF-α) and caspase-3 expression in the ipsilateral (injured) cortex of the adult rats during the recovery period (from 2 to 28 days) after injury. Our results demonstrate that CR prior to CSI suppresses microglial activation, induction of TNF-α and caspase-3, as well as neurodegeneration following injury. These results indicate that CR strongly attenuates the effects of secondary injury, thus suggesting that CR may increase the successful outcome following TBI.
Highlights
Traumatic injury to the brain triggers a complex series of events that can be divided into two phases: primary and secondary injury
caloric restriction (CR) suppresses microglial activation after cortical stab injury (CSI) Activation of microglia characterized by changes in their morphology is the hallmark of secondary injury
The most prominent differences in microglial morphology between ad libitum (AL) and CR group were observed on the 2nd dpi, with numerous activated microglial cells with the large amoeboid or round-shape cell bodies observed in AL group (Fig. 1A and E)
Summary
Traumatic injury to the brain triggers a complex series of events that can be divided into two phases: primary and secondary injury. Damage caused by the primary injury is further augmented by the subsequent pathological processes encompassing the secondary injury. Secondary injury evolves over a period of minutes to hours and days, even to several weeks following initial trauma [reviewed in 1 and 2] and it consists of a multifaceted cascade of inflammatory processes that lead to neuronal degeneration and apoptosis [3]. In response to CNS injury, microglia become active and induce detrimental neurotoxic effects by releasing a diverse set of cytotoxic substances, including proinflammatory cytokine TNF-a [5,6]. TNF-a plays a key role in many physiological and pathological processes including acute and chronic inflammation, and apoptosis [7]. TNF-a produced by microglia is generally thought to induce sequential activation of caspases resulting in the apoptosis [8,9]. Amongst caspases, activated caspase-3 is directly linked to the neuronal cell death following TBI [10]
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