Abstract
Abstract: :
Purpose: We reported that topically applied insulin accumulated in the CSF and CNS in rats. The notion that topically applied peptides can reach the CNS has implications for the treatment of CNS disorders. In order to examine the efficacy of this approach, we determined whether topically applied leptin could accumulate in the CSF. Leptin plays an important role in the hypothalamic regulation of appetite. It has been suggested that leptin resistance at the blood–brain–barrier is responsible, in part, for diet–induced obesity in humans. Thus, the ability to circumvent this barrier by delivering leptin to the brain through the ocular route would have important therapeutic implications. Methods: A 10 microliter drop of a 0.6 mg/ml solution of leptin in Brij78 was applied to the eyes of fasted, anesthetized Lewis rats. Pressure was applied for 1 min, after which another 20 microliters/eye were applied. Untreated fasted and fed rats served as controls. CSF and serum were then collected at various time points and assayed for leptin. Results: Serum and CSF leptin levels were significantly lower in fasted than fed rats. Values were: serum fed = 7.7 ng/ml (n=44), serum fasted = 1.5 ng/ml (n=92), p<0.000001; CSF fed = 230 pg/ml (n=20), CSF fasted = 52 pg/ml (n=34), p<0.0005. Leptin eye drops significantly elevated leptin levels in the CSF – mean+SE (pg/ml) baseline values and values at 5, 10, 20, 30 and 60 min after application were 59+8, 67±39, 300±90, 91±14, 108±24, and 83±4, respectively. Values at 10, 20, and 30 min were significantly greater than baseline (p<0.05 in each case). It was noteworthy that peak leptin levels in the CSF after topical application were similar to those seen in fed rats. Conclusions: Our results showed that leptin accumulated in the CSF after topical application to levels comparable to those seen in fed animals. These data support the contention that the topical route can be used to circumvent the blood–brain–barrier to deliver potentially therapeutic peptides into the CNS.
Keywords: drug toxicity/drug effects