Neurodegenerative disease and optic neuropathy; the MPTP lesson

Purpose: To emphasize lessons learned from the MPTP model of PD for the treatment of optic nerve diseases (OND). The major neurodegenerative diseases (such as Parkinson's (PD)), are known to become symptomatic when already a large number of neurons have died. Knowledge gained from the cellular pathobiology of these disorders has been instrumental for developing new rational therapies. In PD, the original discovery of a neurotoxic animal model ("MPTP") led to an appreciation of the importance of mitochondrial respiratory chain deficit and the role of excitotoxic mechanisms which are currently linked to the action of nitric oxid synthase and induced apoptosis. Each of the three axonal type optic neuropathies, glaucomatous (GOND), ischémie (ION) and Leber's (LHON) share some features with neurodegenerative diseases; the mode of progression, mechanism of cellular damage and limited success of conventional post-hoc therapy, MPTP kills neurons via its conversion product by inhibiting Complex I of the mitochondrial respiratory activity. It is known that the high affinity dopamine (DA) uptake system mediates the uptake of MPTP into targeted DA neurons. This explains why specifically DA cells will be affected. We lack knowledge concerning the topical selectivity and specificity of cellular damage in optic nerve diseases. For instance, in LHON a genetic defect may make mitochondrial mechanisms vulnerable but trigger mechanisms for retinal ganglion cell damage are unknown. In GOND there is a selective loss of the larger neurons, but reasons for this specificity are not yet known. Does excitoxic damage relate to intrinsic electrical-pharmacological properties of some but not all neurons? Are there "environmental" toxic candidates which share the same channels as physiological uptake mechanisms? Conclusion: We must answer questions concerning cellular specific damage to develop OND specific neuroprotective therapies.