Role of Nerve Growth Factor (NGF) on mature and immature neurons in pathological conditions : effects of ocularly applied NGF

Abstract

The eye is a central nervous system structure that is uniquely accessible to local treatment, and through ocular surface it is possible to access the retina, and different brain areas. Macromolecules might indeed be delivered to the retina and transported by the optic nerve to brain by passive trans sclera/conjuntival passage. Animal models of retinal and brain degeneration and ocular treatment could thus serve as tools to investigate whether and how factors, which are anterogradely or retrogradely transported through the optic nerve, might contribute to activate plasticity, neuroprotection, and eventually regeneration. Among these factors, nerve growth factor (NGF), the first discovered and best characterized member of a family of neurotrophic factors, plays a crucial role during development of the visual system during the entire life span, as well as in pathological conditions. NGF ability to exert survival and trophic actions on retina and brain cells when applied on ocular surface as eye drops (ed-NGF) in rat models of streptozotocin-induced (STZ) diabetes, and optic nerve crush (ONC) is described in this thesis. The ONC model was used to disclose critical temporal windows for retina neuronal recovery, and evaluate the effects of NGF treatment. Firstly activated intracellular pathways and modulation of NGF and its receptors expression in the retina and optic nerve were identified in a time course study. Subsequently this experimental model was used to verify the efficacy of intravitreal and ed-NGF application of recombinant human NGF (rhNGF) formulation to act on injured retina. The STZ model was used to evaluate the effects of eye drop NGF treatment on retinal, and cortical neurodegeneration, and manifestation of depression and anxiety phenotype induced by diabetes. The results of these studies are consistent with a growing body of evidence demonstrating that NGF might interfere with pathological processes by exerting regulatory and modulatory effects in neurons and neuronal cell precursors, glial and endothelial cells. Chiefly, the data demonstrate the efficacy of ocular application of NGF to counteract retina and optic e nerve degeneration, and that ed-NGF is able to affect brain areas receiving retina projections similar to what observed following intracerebral NGF infusion. The biochemical and molecular findings also show that ed-NGF hampers the pro-NGF activity, and rebalance the Trk/p75NTR ratio to favor intracellular signals promoting survival, regrowth, and plasticity. In conclusion, our studies indicate that neurodegeneration might be counteracted by increasing the local availability of mature NGF.