Other Protective and Trophic Factors

In addition to the beneficial effects of neurotrophic factor treatments, the ganglioside GM1 has been shown to enhance effects even at minimal concentrations of BDNF. The lazaroids are another intriguing class of compounds that demonstrated a strong trophic effect on promoting the survival of embryonic mesencephalic tissues and their development in vivo. Interestingly, the lazaroids promoted in vivo survival of dopaminergic neurons but did not increase target striatal innervation. These agents have now been incorporated into clinical trials.

Mechanisms of grafted cell death include excito-toxicity and apoptosis. Among the excitotoxic inhibitors, the calcium channel-NMDA receptor antagonist MK-801 is one of the most studied. In vivo, this compound was not able to enhance dopaminergic neuronal survival in the graft, suggesting that cell death in the grafts may not be due to excitotoxicity. The other mechanism of cell death in transplants, apoptosis, is under intense scrutiny because caspase inhibitors seem to reduce neuronal death in the grafts. Furthermore, the combination of pretreatment with a caspase inhibitor and a lazaroid may have a significantly higher positive effect on transplanted dopami-nergic neurons.

Finally, debates in neural cell grafting gravitate around the potentially beneficial effects of new generation immunosupressive drugs that have been shown to be less toxic to the brain. A representative member of this family is the FK-506 drug. This compound, together with CsA and rapamycin (approved for clinical trials), binds to receptors called immunophi-lins. Many of the immunophilin ligands have be shown to possess neurotrophic activities. This field is under intense scrutiny, especially since immunophilins have been proven to be abundant in the brain. Among the newer members of the immunophilin ligand family, the non-immunosuppressive drug GPI-1046 shows much promise in promoting regenerative neuritic growth from surviving neurons in various CNS lesions. Furthermore, the immunophilin ligand V-10,367 has been shown to specifically increase the growth of dopaminergic neurons (mostly neurite branching) and protect against MPTP lesioning, in a manner superior to FK-506.

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