Design-Based Stereology Reveals Motoneuron Preservation Following VEGF Infusion
Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mertens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005;8(1):85-92. doi: 10.1038/nn1360.
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of spinal and bulbar motoneurons. Previous attempts using neurotrophic factors failed to yield significant therapeutic benefit, partly due to limited delivery to target neurons. Vascular endothelial growth factor (VEGF) had shown neuroprotective properties in genetic and viral delivery models.
Hypothesis: This study hypothesized that continuous intracerebroventricular (i.c.v.) delivery of recombinant VEGF protects motoneurons and prolong survival in rat models of ALS.
Methods: The authors stereotactically implanted osmotic minipumps to infuse VEGF into the lateral ventricle of SOD1^G93A rats and used radiolabeled VEGF to assess biodistribution. Motor behavior and survival were monitored. For histological analysis, motoneurons in the facial nucleus and spinal cord were quantified using design-based stereology with Stereo Investigator, and axons were assessed on toluidine blue–stained ventral root sections.
Results: Continuous i.c.v. VEGF delivery delayed disease onset, improved motor performance and extended survival by up to 22 days. Stereological analysis revealed that VEGF doubled facial motoneuron numbers and preserved large cervical α-motoneurons and ventral root axons. VEGF also maintained neuromuscular junction innervation.
Conclusions: Continuous i.c.v. VEGF administration confers robust neuroprotection in ALS models, preserving motoneurons and neuromuscular connectivity and demonstrating therapeutic potential for human neurodegenerative disease.
