Ischemic stroke results from an obstruction of a blood vessel supplying blood to the brain. The brain is an organ extremely sensitive to reduction of oxygen and energy, and brain damage is already caused after short periods of blocked blood flow. The effects of a stroke depend on the location of obstruction and the extent of the brain tissue affected. Stroke is a major cause of death and reduction of life quality in the elderly population, and there is no drug treatment that would promote functional recovery after stroke.
We have established novel stroke models, where ischemic injury is restricted to the cortex, enabling studies of functional recovery, brain adaptations, neuronal rearrangements, and transdifferentiation of non-neuronal cells (Mätlik et al., 2015 Cell Death and Disease), and by a recently developed peri-infarct targeting technique (Mätlik et al. 2014, J. Neurosci Methods) we can overexpress proteins at the place where most tissue recovery occurs. By combining biochemical assays to behavioral assays, we are able to study the recovery process. Besides in vivo assays, we have also established in vitro models of ischemia-reperfusion injury in primary neuronal cultures. We are focused on neurotrophic factors, endoplasmic reticulum stress, and inflammation that occurs days after stroke.
For acute neuroprotection we have been interested in mesencephalic astrocyte-derived neurotrophic factor (MANF). When using recombinant proteins (Airavaara et al., 2009 J Comp Neurol) or overexpression by adeno-associated virus vectors we have found MANF to protect the brain tissue, if it is delivered before the stroke. We have also identified important MANF structures for neuroprotective efficacy (Mätlik et al. 2015, Cell Death and Disease).
More recently, we have started to study the role of MANF in repair and generation of cerebral cortex. We explored the role of MANF in cortical development in the mouse, and we have found that MANF is essential for neurite outgrowth, differentiation, and migration of developing neurons (Tseng et al., 2017, eNeuro; Tseng et al., 2018 Molecular Therapy). Moreover, we have shown that MANF increases the number of developing neurons in the peri-infarct cortex after cortical ischemia-reperfusion injury.
Indeed, this have led us to study the delayed events in stroke, and we try to identify and validate novel drug targets from inflammation and regeneration processes to hasten the recovery after stroke. We have found that tissue recovery is a very slow process and phagocytic cells can be found in the brain even months after the ischemic injury (Anttila et al., 2018 eNeuro). We think that manipulations of these delayed events can result in facilitation of tissue and behavioral recovery and restoration of functional circuits. Recently we found that naloxone, a drug used as an antidote for opioid overdose, can hasten functional recovery when administered intranasally after stroke and modulate the inflammatory response (Anttila et al., 2018 eNeuro). In another study we showed that post-stroke peri-infarct targeting with MANF is facilitating functional recovery and it transiently increases the number of phagocytic cells in the peri-infarct regions (Mätlik et al. 2018, Science Advances).