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V. Lam, G. Patsiopoulos, S. Koevary; Topically Applied Insulin Accumulates in the Lumbar Cistern in Rats . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4437.
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Purpose: We previously reported that insulin accumulated not only in the retina and optic nerve following ocular application, but also in the cerebrospinal fluid (CSF) within the cisterna magnum, and in the brain. The purpose of this study was to determine the extent to which this insulin permeated the CSF space by sampling the CSF from the lumbar cistern. Methods: A 10 microliter insulin eye drop (0.75% porcine insulin) was applied to both the left and right eyes of overnight fasted female Lewis rats. The animals were anesthetized 15 minutes later with ketamine/xylazine and at 20 minutes post eye drop application, CSF was extracted from the lumbar cistern through a 25G canula inserted between the 3rd and 4th lumbar vertebrae. The rats were then sacrificed by decapitation and blood was collected. Control rats included a group that did not receive an eye drop (baseline) as well as another group that received a total of 20 microliters of the insulin eye drop solution sublingually. The serum and CSF samples were assayed for the presence of porcine insulin using an ELISA kit, and values were expressed as ng/ml. Results: The baseline CSF porcine insulin concentration (mean +/- SEM) was 0.09 +/- 0.01 (N=12), reflecting the minimal crossreactivity of porcine with rat insulin in the ELISA assay. The insulin concentrations in the lumbar CSF in rats that received sublingual or eye drop insulin treatment were 0.15 +/- 0.04 (N=18) and 0.27 +/- 0.06 (N=15; p<0.01 compared to baseline), respectively. Serum insulin levels were elevated in both rats that received sublingual insulin (0.25 +/- 0.1) and in eye drop treated rats (2.5 +/- 0.08) compared to baseline animals (0.09 +/- 0.02), though these serum elevations were just shy of being statistically significantly. Conclusions: Our results showed that topically applied insulin accumulated in the lumbar CSF. Since insulin levels were also elevated somewhat in the CSF of rats that received sublingual insulin, and since serum insulin levels were elevated in both of these groups, it is theorized that at least some of this CSF insulin was derived from the circulation. What fraction of this insulin actually reflects diffusion of topically applied insulin into the CSF surrounding the optic nerve and its dispersal into the lumbar cistern remains to be investigated. These data have important implications for the field of CNS drug delivery and also force a reexamination of the causes of the systemic side effects of topically applied medications.
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