Investigation of the effects of brain-derived neurotrophic factor on neuroinflammation triggered by cortical spreading depression

Cortical spreading depression (CSD) is not just an experimental phenomenon, but also seen in the conditions such as migraine aura, ischemic stroke, acute brain trauma, intracranial hemorrhage and epilepsy in people. It has been demonstrated by many studies that an inflammatory response is triggered by CSD and CSD-related changes recovers spontaneously in healthy brain tissue. Brain-derived neurotrophic factor (BDNF) is a neurotrophin thought to have some neuroprotective and anti-inflammatory effects. The relationship between the inflammatory response triggered by multiple CSDs and BDNF is unknown. In this study, it is aimed to investigate the hypothesis that BDNF is effective in the inhibition of inflammatory response induced by CSD. To test this hypothesis firstly, the changes in the levels of BDNF and proBDNF proteins as well as pro-inflammatory cytokines IL-1β and TNF- in the early period (1st, 2nd and 6th hours) after multiple CSDs were investigated. We found that at the 1st hour after multiple CSDs, BDNF protein levels of parietal cortex increased compared to contralateral cortex and at the 6th hour it is increased when compared to both contralateral and sham operated cortices. ProBDNF protein level is found to be increased compared to both contralateral and sham operated parietal cortices ant the 1st and 6th hours. Immunohistochemically, BDNF protein-labeled cells were also labeled by astrocyte markers after multiple CSDs, so that the increase in BDNF level is thought to be originated from astrocytes. It was found that neuronal IL-1β, which was normally labeled as nuclear, was switched to cytoplasm after the 1st hour after multiple CSDs, and its nuclear form was increased at the 6th hour. Similarly, normally nuclear-labeled neuronal TNF- was switched to the cytoplasm at the 2nd hour after multiple CSDs, and at the 6th hour there was an increase in nuclear labeling again. Secondly, the effect of increased BDNF protein levels on the multiple CSD-induced inflammatory processes were investigated by increasing the levels of cortical BDNF with intracerebroventricular (ICV) injection of recombinant BDNF protein prior to multiple CSD triggering. By ICV injection of recombinant BDNF protein, BDNF protein levels of the parietal cortex was found to be increased compared to both the contralateral and sham operated cortices. No significant difference was found in the percentages of IL-1β-labeled cells at the 1st and 2nd hours after the multiple CSDs between the groups of ICV BDNF and ICV distilled water injections. To investigate the effect of BDNF protein on CSD-induced inflammation, non-invasive methods to increase BDNF protein levels are needed. The finding of this study is BDNF protein, which has previously been shown to have anti-inflammatory effects, increases after multiple CSDs supporting the hypothesis that BDNF plays a role in the CSD-induced inflammation. Keywords: cortical spreading depression, brain-derived neurotrophic factor, neuroinflammation, interleukin-1-beta, tumor necrosis factor-alpha