Abnormal centrifugal axons in streptozotocin-diabetic rat retinas.

In mammalian retinas, centrifugal axons contain immunore-active (IR) histamine and originate from neurons in the hypothalamus.1-3 In macaque monkey retinas, histamine-IR axons emerge from the optic nerve head, run in the optic fiber layer, and terminate in the IPL, sometimes adjacent to retinal blood vessels.4 Histamine released from these centrifugal axons may promote the breakdown of the blood–retinal barrier (BRB) in diabetic retinopathy. In patients with diabetes, microaneurysms commonly form in the central retina, temporal to the fovea,5 and this area has the highest density of histamine-IR centrifugal axons in normal macaque retinas.4 In rats, histamine applied intravitreally increases the permeability of the BRB.6 Histamine also decreases the expression of the tight junction protein ZO-1 in cultured bovine retinal vascular endothelial cells, and this effect would be expected to increase vessel permeability.7 Histamine antagonists reduce the thickening of the retinal capillary basement membranes8 and prevent increases in retinal vascular permeability in rats with streptozotocin-induced diabetes (streptozotocin-diabetic rats).9 In patients with insulin-dependent diabetes who have mild, nonproliferative diabetic retinopathy, a combination of histamine H1 and H2 receptor antagonists administered for 6 months significantly decreases the permeability of the BRB.10 However, patients with diabetic macular edema do not benefit from 1 year of treatment with an H1 antagonist alone.11 The activity of retinal histidine decarboxylase, the enzyme that synthesizes histamine, is markedly increased in experimental diabetic rats.12 Therefore, the purposes of this study were to identify the cells that express histidine decarboxylase in diabetic rat retinas and to determine whether diabetes alters retinal histaminergic axons.