Background. Despite recent advancements in neuroscience, and ever-emerging novelties in the field of drug delivery, the blood brain barrier is still considered a major obstacle that critically limits the delivery to the brain of hydrophilic drugs or those with modest or weak hydrophobic character. Brimonidine, a selective alpha-2 agonist, is a widely used ocular hypotensive agent with promising merits as neuroprotectant. Aim. To demonstrate the efficient delivery to the brain of Brimonidine following ocular administration and to elucidate the route of non-systemic drug flow along the eye-brain axis. Methods. Brimonidine was used as a probe to study the eye and brain pharmacokinetics following topical ocular administration of one droplet of the radio-labeled drug. Animals were sacrificed at different time points following the administration of single 0.2% 3H-Brimonidine droplet to the rabbit eye. Brain and eyes were dissected and selected brain and eye tissues, as well as systemic blood samples, were processed for detecting the concentration of radio-labeled Brimonidine. Fluorescent-labeled Dextran with molecular weight of 40 kDa was used as a probe to elucidate the route of the non-systemically mediated eye-to-brain drug flow following periocular administration. Results. Brimonidine accumulation in studied intracranial tissues was significant already at 5 minutes following single ocular administration while the detected Brimonidine levels in the systemic blood were very low at all time points. Evaluation by fluorescent microscopy showed that 40 kDa fluorescent-labeled Dextran that was administered to the periocular space didnt permeate the ocular barriers and was flowing through veins that drain the eye and orbital tissues towards the intracranial cavernous sinus. Tissue sections that included the eye and its major vessels showed extensive accumulation in veins but with no signal of the fluorescented probe inside the ciliary artery, which corresponds to non-significant flow of the probe through the systemic circulation. Conclusion. Brimonidine, a non-toxic agent to the eye with well appreciated therapeutic merits, can accumulate in intracranial tissues at significant concentrations already at few minutes after simple ocular administration with very low systemic accumulation. Our results suggest an efficient method for the extension of Brimonidine therapeutic merits to the brain while avoiding systemic side effects.

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