Poststroke delivery of MANF promotes functional recovery in rats

Stroke is the most common cause of adult disability in developed countries, largely because spontaneous recovery is often incomplete, and no pharmacological means to hasten the recovery exist. It was recently shown that mesencephalic astrocyte-derived neurotrophic factor (MANF) induces alternative o...

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Published in:Science advances 2018-05, Vol.4 (5), p.eaap8957-eaap8957
Main Authors: Mätlik, Kert, Anttila, Jenni E, Kuan-Yin, Tseng, Smolander, Olli-Pekka, Pakarinen, Emmi, Lehtonen, Leevi, Abo-Ramadan, Usama, Lindholm, Päivi, Zheng, Congjun, Harvey, Brandon, Arumäe, Urmas, Lindahl, Maria, Airavaara, Mikko
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Behavior, Animal
Brain Ischemia - complications
Dependovirus - genetics
Disease Models, Animal
Diseases and Disorders
Gene Expression
Genetic Vectors - genetics
Health and Medicine
Humans
Magnetic Resonance Imaging
Male
Nerve Growth Factors - genetics
Nerve Growth Factors - metabolism
Rats
SciAdv r-articles
Stroke - diagnosis
Stroke - etiology
Stroke - metabolism
Stroke Rehabilitation
Transduction, Genetic
Transgenes
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Summary:Stroke is the most common cause of adult disability in developed countries, largely because spontaneous recovery is often incomplete, and no pharmacological means to hasten the recovery exist. It was recently shown that mesencephalic astrocyte-derived neurotrophic factor (MANF) induces alternative or M2 activation of immune cells after retinal damage in both fruit fly and mouse and mediates retinal repair. Therefore, we set out to study whether poststroke MANF administration would enhance brain tissue repair and affect behavioral recovery of rats after cerebral ischemic injury. We used the distal middle cerebral artery occlusion (dMCAo) model of ischemia-reperfusion injury and administered MANF either as a recombinant protein or via adeno-associated viral (AAV) vector. We discovered that, when MANF was administered to the peri-infarct region 2 or 3 days after stroke, it promoted functional recovery of the animals without affecting the lesion volume. Further, AAV7-MANF treatment transiently increased the number of phagocytic macrophages in the subcortical peri-infarct regions. In addition, the analysis of knockout mice revealed the neuroprotective effects of endogenous MANF against ischemic injury, although endogenous MANF had no effect on immune cell-related gene expression. The beneficial effect of MANF treatment on the reversal of stroke-induced behavioral deficits implies that MANF-based therapies could be used for the repair of brain tissue after stroke.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aap8957