Neuroprotective efficacy of FR901459, a novel derivative of cyclosporin A, in in vitro mitochondrial damage and in vivo transient cerebral ischemia models.

Abstract

The immunosuppressant cyclosporin A (CsA) has been shown to exert potent neuroprotective effects, possibly via the inhibition of calcineurin and mitochondrial permeability transition pore formation. Here, we investigated the neuroprotective profile of a novel derivative of CsA, FR901459, by evaluating its effects against in vitro mitochondrial damage and in vivo brain damage in transient global or focal cerebral ischemia models, in comparison with those of CsA. Efficacy of calcineurin inhibition was estimated from its immunosuppressive effect on the mixed lymphocyte reaction. Results showed that the immunosuppressive effect of FR901459 was approximately 7-fold less potent than that of CsA. In contrast, FR901459 suppressed Ca(2+)-induced mitochondrial swelling measured in isolated liver mitochondria with greater potency than CsA. Further, FR901459 showed approximately 30-fold greater neuroprotective potency than CsA against neuronal cell damage induced by thapsigargin in SH-SY5Y cells. In a transient global cerebral ischemia model in gerbils, FR901459 showed the dose-dependent suppression of neuronal cell death, while FR901459 was less efficacious than CsA. In a rat transient focal ischemia model, FR901459 tended to reduce brain damage on both intravenous injection as well as intracerebroventricular infusion, but with less efficacy than CsA which significantly reduced the damage. These findings suggest that FR901459 exerts a potent neuroprotective effect by inhibiting mitochondrial damage in vitro, but that in in vivo transient cerebral ischemia, its immunosuppressive component which possibly acts via the inhibition of calcineurin may play a more important role in attenuating brain damage than its inhibitory effect against mitochondrial damage.

• Authors: Yuko Muramatsu, Yasuhisa Furuichi, Nobuteru Tojo, Akira Moriguchi, Takuya Maemoto, Hirohisa Nakada, Motohiro Hino, Nobuya Matsuoka
• Journal: Brain research (Brain Res) Vol. 1149 Pg. 181-90 (May 29 2007) ISSN: 0006-8993 [Print] Netherlands
• PMID: 17391653 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Neuroprotective Agents
• FR 901459
• Cyclosporine

Topics

• Animals
• Cell Line, Tumor
• Cyclosporine (pharmacology)
• Gerbillinae
• Humans
• Hypoxia, Brain (etiology, prevention & control)
• In Vitro Techniques
• Ischemic Attack, Transient (complications, drug therapy)
• Lymphocyte Culture Test, Mixed
• Mitochondria (drug effects, pathology)
• Neuroprotective Agents (pharmacology)
• Rats