Cannabis e glaucoma Dott.ssa Anna Porcella Istituto di Neurogenetica e Neurofarmacologia Consiglio Nazionale delle Ricerche, Cagliari Roma 6 ottobre 2001 UNIVERSITÀ "LA SAPIENZA" Usi innovativi di farmaci antichi L'attuale rivalutazione medica della Cannabis e dei cannabinoidi

Glaucoma A condition of the eye where the intraocular pressure is elevated beyond the limit that will permit normal function of the optic nerve.  Almost 100 million people affected world wide  7 million totally blind due to the progression of their glaucomas

PRIMARY OPEN ANGLE GLAUCOMA (POAG) Open anterior chamber The obstruction of the trabecular meshwork – Schlemm’s canal system blocks the outflow of aqueous humor

OUTFLOW OF AQUEOUS HUMOR

Marijuana smoking was first reported to reduce intraocular pressure (IOP) in 1971 (Hepler and Frank, 1971) Cloning of CB1 and CB2 receptors and the discovery of Endocannabinoids has opened the field for research into their physiological roles Distribution studies in both the brain and the periphery have shown that in some tissues these receptors are colocalized

IRIS ANTERIOR CHAMBER CORNEA SCLERA SCHLEMM’S CANAL SYSTEM LENS CILIARY BODY CILIARY MUSCLE DIAGRAMMATIC CROSS SECTION OF THE ANTERIOR CHAMBER

CB1 mRNA IN THE RAT EYE Porcella et al. Mol. Br. Res, 1998

CB1 mRNA IN THE HUMAN EYE Porcella et al. Eur. J. Neurosci, 2000

CB1 PROTEIN IN THE HUMAN EYE Porcella et al. Eur. J. Neurosci, 2000

 2 Adrenoreceptor agonists  2 Adrenoreceptor antagonists Prostaglandin Agonist Dopamninergic agonist Cholinergic Agonist Carbonic Anhydrase Inhibitors Guanylate Cyclase Activators Adenosine agonist NMDA Antagonist ARMAMENTARIUM OF DRUGS IN USE TO TREAT GLAUCOMA Cannabinoids ?

Natural cannabinoids Endogenous cannabinoids  9 -THC  8 -tetrahydrocannabinol CannabinolCannabidiol Anandamide2-AG

Synthetic cannabinoids Nabilone WIN 55,212-2 CP 55,940HU 210 SR141716A LY Palmitoyl-EA (CB2 only) SR144528

Porcella et al. Eur. J. Neurosci, 2001 EFFECT OF TOPIC WIN ON IOP OF GLAUCOMATOUS PATIENTS

THE HIGH LEVEL OF CB1 mRNA AND PROTEIN IN THE CILIARY BODY SUGGEST A LOCALIZED VASODILATION BY CANNABINOIDS IN ADDITION INHIBITION OF PRESYNAPTIC Ca ++ CHANNELS BY CANNABINOIDS MAY REDUCE NORADRENALINE RELEASE IN THE EYE AND THE PRODUCTION OF AQUEOUS HUMOR SR141716A ANTAGONIZES IOP LOWERING EFFECTS OF CANNABINOIDS IN RABBITS SUGGESTING A DIRECT CB1 INVOLVEMENT IN THIS MECHANISM HOWEVER THE MECHANISM BY WHICH CANNABINOIDS ARE ABLE TO DECREASE IOP REMAINS TO BE FURTHER ELUCIDATED SUMMARY (1)

SUMMARY (2) IOP LOWERING EFFECTS OF TOPIC WIN IN GLAUCOMATOUS PATIENTS ARE TIME AND DOSE DEPENDENT SYNTHETIC CB1 AGONISTS SHOULD DESERVE FURTHER RESEARCH AND CLINICAL DEVELOPMENT