Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques
Treatment strategies based on transfer of genes, molecules, or cells to the central nervous system are summarized. When neurons are already degenerated, functional compensation can be effected by grafts of syngeneic or allogenic tissue to the target area. This technique is undergoing clinical trials in Parkinson’s disease. Before degeneration has occurred, it may be possible to rescue “stressed” neurons, and stimulate terminal outgrowth using treatment with neurotrophic factors. Such approaches, with an emphasis on the NGF family of neurotrophins and their receptors, are reviewed. Finally, new molecular biology techniques may permit the transfer of genes directly into non-dividing cells of the central nervous system. These three approaches may have a more general applicability, and become important not only in neurodegenerative diseases, but also in other afflictions of the nervous system such as ischemia, stroke and injury.
While axonal regeneration is an effective and clinically important mechanism in the peripheral nervous system, it is a well-established fact that long nerve fiber pathways do not regenerate in the adult mammalian central nervous system. The reason for this difference long remained unknown, but the elegant experiments of Aguayo and collaborators (David and Aguayo, 1981) have demonstrated that adult CNS axons are able to elongate efficiently if given the appropriate environment, such as a section of peripheral nerve. The discrepancy between regenerative capacity in CNS and PNS has at least three possible bases: (1) production of neurotrophic factors by Schwann cells but not oligodendroglial cells, (2) the production of nerve growth inhibitory factors by oligodendroglial but not Schwann cells, or (3), scar formation to a greater extent in the CNS than in the PNS. It now appears as if all three possibilities are true. There are relatively effective regenerative mechanisms for peripheral nerve injury, but the extreme complexity of the central nervous system and precise regulation of central connectivity has led to an absence of such regenerative capacity. As longevity has increased in modern society, the need for reparative intervention for neurodegenerative diseases has increased commensurately.
While research during the last two decades has not yet provided us with methods to effectively stimulate regeneration of long fiber tracts in the central nervous system, it has led to the development of two other principal repair strategies. The first is a cell replacement strategy; neurons that have been lost can sometimes be functionally replaced by other cells such as embryonic neurons which are implanted, not at the original site of such nerve cell bodies, but directly into their axonal target regions. With this strategy one avoids the necessity of regenerating a long axon pathway, obviously with loss of the original circuitry, but there is a gain of new nerve terminals. The second approach is applicable before neurons have died, and focuses on prevention of “stressed” neurons from dying and stimulation of nerve terminals from remaining neurons using neurotrophic factors. Obviously, these two principles can be combined. In the following, we shall discuss some of the recent animal research for treatment with grafts and growth factors, as well as comment upon ongoing clinical trials.
One may look at reparative strategies as various ways of transfering molecules or cells to the brain to obtain long-lasting effects. Thus molecular and cellular transfer techniques fundamentally differ from current treatment strategies of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Current treatments attempt to increase dopamine and cholinergic neurotransmission, respectively, by pharmacological means such as administering a dopamine precursor, an acetylcholinesterase inhibitor, or various direct and indirect agonists. These treatments may be somewhat effective as long as the drugs are taken regularly, but the positive effects disappear immediately upon drug withdrawal. Moreover, tolerance and side effects are common problems.
KeywordsNerve Growth Factor Neurotrophic Factor Schwann Cell Dopamine Neuron Adult Mammalian Central Nervous System
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