Cyclosporine-A (CsA) and its analogues have been shown to be neuroprotective in experimental models of neurological disorders, including Parkinson?s disease (PD) and stroke. Because CsA does not easily cross the blood brain barrier (BBB), a high dose (i.e., > 10 mg/kg in rats) and chronic administration of the drug may be necessary to produce beneficial effects. However, immunosuppressant side effects are associated with such a high dose CsA regimen. Recently, the bradykinin receptor, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. In the present study, 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 that does not produce immunosuppression) or CsA in combination with Cereport (9 ug/kg). At one month post-lesion, amphetamine-induced rotational tests revealed that lesioned animals that received either vehicle infusion only (controls) or CsA alone exhibited 244+/-52 and 229+/-40 (mean ? S.E.) full turns over 30 mins, respectively, while animals that received CsA + Cereport displayed 78+/-26 mean rotations. Similarly, elevated body swing tests revealed that lesioned animals that received either vehicle infusion only or CsA alone exhibited 92.5+/-10 and 95+/-7.5 (mean+/-S.E.%) biased swings, respectively, whereas lesioned animals that received CsA + Cereport displayed 55+/-12.5% mean biased responses. Differences in both motor behaviors, between vehicle or CsA alone and CsA + Cereport, were statistically significant. Histological analyses using TH immunohistochemistry supported the observed attenuation of 6-OHDA-induced behavioral abnormalities. Near complete depletions of nigral TH-ir neurons were noted in lesioned animals that received vehicle infusion or CsA alone. In contrast, lesioned animals that received CsA + Cereport exhibited a 50-70% sparing of nigral TH-ir neurons. Similar observations were noted in striatal TH-ir fiber density. These results suggest that Cereport permitted the protective effects of low dose CsA to be manifested. The safe and effective administration of combined CsA and Cereport offers a novel way of producing protective effects in the central nervous system without the toxic liabilities of high dose CsA. In order to examine whether increased bradykinin receptors in the brain underlied the observed neuroprotection by combined Cereport and CsA treatment, human bradykinin B2 receptor-overexpressing (HBKR) transgenic mice were subjected to MPTP lesions (another model of Parkinson's disease). HBKR or wild-type-mice were randomly assigned to 30 mg/kg MPTP (daily dose, i.p., for 2 consecutive days) or vehicle. Histological analyses at 10 days after the drug administration revealed that HBKR or wild-type mice that received MPTP displayed significant reductions in striatal TH mean optical density compared to HBKR or wild-type mice that received vehicle. There was no significant difference in the striatal TH immunoreactivity between MPTP-treated HBKR and wild-type mice. These results suggest that increased bradykinin receptors in the brain did not produce neuroprotective effects against MPTP-induced dopaminergic lesions.
| Borlongan, Cesario V; Emerich, Dwaine F; Hoffer, Barry J et al. (2002) Bradykinin receptor agonist facilitates low-dose cyclosporine-A protection against 6-hydroxydopamine neurotoxicity. Brain Res 956:211-20 |
