The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte-Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity.

Abstract

Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.

• Authors: Ahmet Burak Caglayan, Mustafa Caglar Beker, Elif Sertel Evren, Berrak Caglayan, Ülkan Kilic, Nilay Ates, Aysun Caglayan, Muhammed Furkan Dasdelen, Thorsten Roland Doeppner, Mart Saarma, Dirk Matthias Hermann, Ertugrul Kilic
• Journal: Translational stroke research (Transl Stroke Res) Vol. 14 Issue 2 Pg. 263-277 (04 2023) ISSN: 1868-601X [Electronic] United States
• PMID: 35583716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Dopamine
• MANF protein, mouse
• Nerve Growth Factors
• cdnf protein, mouse

Topics

• Animals
• Mice
• Astrocytes (metabolism)
• Axons
• Brain (metabolism)
• Dopamine (metabolism)
• Nerve Growth Factors (metabolism, pharmacology)
• Stroke