Assessment of cerebroprotective and neuroregenerative properties of rhFGF18 and rhGDF11.

Despite advances in prevention, stroke remains the second-leading cause of death and third-leading cause of disability globally. While several growth factor cerebroprotective therapeutics, including rhGDF11 and rhFGF18, have shown promise, tPA remains the only treatment with established efficacy, despite its associated risk of hemorrhage and limited effect on mortality.

Ischemia was simulated in 250-300g m/f Wistar rats via middle cerebral artery occlusion (2 hours, Day 1). PBS and 100ug/kg/hr rhFGF18 were administered intravenously (0.5mL/hour, 3 hours); rhGDF11 was administered intraperitoneally (5-daily, 100ug/kg injections in 100uL PBS, starting Day 7). Morris water maze was performed on Days 7, 21, and 42. Tissue sections were collected on Days 21 and 42 to assess morphology (Nissl stain), acetylcholinesterase (AChE) fiber density and activity, as well as metabolic parameters (succinate / lactate dehydrogenases (SDH/LDH)).

By Day 7, water maze times in the control group, rhFGF18, and rhGDF11 increased by 38.3%, 2.1%, and 23.1% relative to baseline, with rhFGF18 achieving statistical significance over PBS. Fraction of neurons with abnormal morphology decreased in all groups toward Day 42 and was lowest for rhFGF18. AChE-positive fiber density appeared to increase over time in rhFGF18 treated animals, remained unchanged for rhGDF11, and declined in PBS control; similar changes were observed in the level of AChE enzymatic activity. Metabolic increases were greatest in rhGDF11 treated animals, as evidenced by an increase in SDH and LDH activity, with both rhFGF18 and rhGDF11 achieving improvements over PBS. Finally, rhFGF18 appeared to promote a trend for reduced mortality relative to PBS (5.6%, 95% CI [27.3%, 0.1%] vs. 22.2%, 95% CI [47.6%, 6.4%]).

Early intervention with rhFGF18 analog appears cerebroprotective with potential benefits in survival, recovery of motor and memory function, as well as neuronal viability and metabolic activity.