Bradykinin receptor agonist facilitates low-dose cyclosporine-A protection against 6-hydroxydopamine neurotoxicity

Abstract

Cyclosporine-A (CsA) is neuroprotective in animal models of Parkinson's disease (PD), Huntington's disease and stroke. Because CsA does not easily cross the blood-brain barrier (BBB), high doses (i.e. >10 mg/kg in rats) and chronic administration may be necessary to produce beneficial effects. However, immunosuppressant side effects (including nephrotoxicity and hepatotoxicity) are associated with such CsA dosing regimens. The bradykinin B2 receptor agonist, Cereport (labradimil and formerly called RMP-7), transiently increases the permeability of the BBB to facilitate delivery of drugs to the CNS. Here we examined the effects of co-administration of CsA and Cereport in the unilateral 6-OHDA model of PD. Animals were pretreated with vehicle, CsA alone (1 mg/kg, a low dose without either immunosuppressive or neuroprotective effects, or 10 mg/kg, a high dose that produces both immunosuppression and neuroprotection), or CsA (1 mg/kg) in combination with Cereport (9 microg/kg). Behavioral analyses, using elevated body swing and amphetamine-induced rotational tests, revealed that a low dose of CsA was neuroprotective when combined with Cereport, but not when given alone. Tyrosine hydroxylase immunohistochemistry demonstrated that while near complete (>90%) depletions of nigral TH-ir neurons were noted in lesioned animals that received vehicle infusion or low-dose CsA alone, lesioned animals that received low-dose CsA+Cereport exhibited a significant sparing of nigral TH-ir neurons and a marked reduction in the loss of striatal TH-ir fibers. The safer and effective administration of lower doses of CsA combined with enhanced BBB permeability using Cereport, offers a novel way of producing protective effects in the CNS without the toxic liabilities of high-dose CsA.