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A stroke affecting the somatosensory pathway can trigger central post-stroke pain syndrome (CPSP). The symptoms often include hyperalgesia, which has also been described in rodents after the direct damage of the thalamus. Previous studies have shown that hemorrhagic stroke or ischemia caused by vasoconstriction in the thalamus induces increased pain sensitivity. We investigated whether inducing secondary damage in the thalamus by a cortical stroke causes similar pain hypersensitivity as has previously been reported with direct ischemic injury. We induced a focal cortical ischemia-reperfusion injury in male rats, quantified the amount of secondary neurodegeneration in the thalamus, and measured whether the thalamic neurodegeneration is associated with thermal or mechanical hypersensitivity. After one month, we observed extensive neuronal degeneration and found approximately 40% decrease in the number of NeuN+ cells in the ipsilateral thalamus. At the same time, there was a massive accumulation—a 30-fold increase—of phagocytic cells in the ipsilateral thalamus. However, despite the evident damage in the thalamus, we did not observe thermal or mechanical sensitization. Thus, thalamic neurodegeneration after cortical ischemia-reperfusion does not induce CPSP-like symptoms in rats, and these results suggest that direct ischemic damage is needed for CPSP induction. Despite not observing hyperalgesia, we investigated whether administration of cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) into the ipsilateral thalamus would reduce the secondary damage. We gave a single injection (10 µg) of recombinant CDNF or MANF protein into the thalamus at 7 days post-stroke. Both CDNF and MANF treatment promoted the functional recovery but had no effect on the neuronal loss or the amount of phagocytic cells in the thalamus.

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF overexpression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)+cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the peri-infarct zone increased the recruitment of DCX+cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.