Tirilazad mesylate improves survival of rat and human embryonic mesencephalic neurons in vitro.
The survival rate of embryonic dopamine (DA) neurons after transplantation to the striatum is only 5-20%. Therefore, mesencephalic tissue from several donors needs to be implanted in a parkinsonian patient to induce a therapeutic improvement. Lazaroids are a group of neuroprotective compounds which inhibit lipid peroxidation. Previously, two lazaroids (U-74389G and U-83836F) have been found to improve the survival of both cultured and grafted rat DA neurons. The only lazaroid approved for human use is tirilazad mesylate. The objective of the present study was to explore the effects of tirilazad mesylate on DA neuron survival in cultures of rat ventral mesencephalon and its capacity to promote the in vitro cell viability of embryonic rat and human mesencephalic tissue, treated and dissociated in the same way as in clinical trials. After 7 days in vitro, the number of tyrosine hydroxylase-immunopositive, presumed DA neurons was 140% higher in rat cultures treated with 0.3 microM tirilazad mesylate than that in control cultures. Rat and human cell suspensions supplemented with tirilazad mesylate maintained a high degree of viability for several hours longer than control suspensions. These results indicate that tirilazad mesylate promotes the survival of both rat and human embryonic mesencephalic neurons in vitro. Tirilazad mesylate can be administered clinically and may become a useful tool for increasing survival of grafted DA neurons in patients, thereby reducing the needed quantity of human donor tissue.
Othberg
A
A
Department of Clinical Neuroscience, Wallenberg Neuroscience Center, Lund, Sweden.
Keep
M
M
Brundin
P
P
Lindvall
O
O
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D000975:Antioxidants; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011281:Pregnatrienes; D014446:Tyrosine 3-Monooxygenase; C053355:tirilazad