Raloxifene through its Cannabinoid Type-2 Receptor Inverse Agonism Mitigates Visual Deficits and Pathology after Impact TBI

Abstract

Purpose : We have previously shown that treatment for 2 weeks with the cannabinoid type-2 receptor (CB2) inverse agonist SMM189 attenuates the visual deficits and retinal pathology produced by closed-head focal cranial blast in mice, by modulating the otherwise deleterious effect of microglia in secondary pathogenic processes. SMM189, however, has not yet been approved for human use. Raloxifene is FDA approved (as an estrogen receptor drug to treat osteoporosis) but also acts as a CB2 inverse agonist, and similarly attenuates the visual deficits and retinal pathology produced by closed-head focal cranial blast in mice. Here we assessed if raloxifene also reduces the visual deficits and retinal pathology that result from impact traumatic brain injury (TBI).

Methods : Single impact TBI was produced in anesthetized male C57BL/6 mice using an Impact One Stereotaxic Impactor (Leica Biosystems, Buffalo Grove, IL) at a strike velocity of 5 m per second, strike depth of 1.0 mm, and dwell time of 200 milliseconds, to the shaved mouse head at 1.5 mm caudal to Bregma and centered on the midline. Mice were injected with vehicle or raloxifene at 5 or 10 mg/kg daily for 2 weeks. Sham male mice were anesthetized, secured in the Impact One device but not impacted, and subsequently injected with vehicle. Functional tests at >1 month assessed visual acuity and contrast sensitivity, the scotopic ERG, light aversion, and the pupil light reflex. Morphological analysis assessed optic nerve injury.

Results : We found that central midline impact TBI yielded bilateral deficits in visual acuity and contrast sensitivity, a reduction in the B-wave amplitude of the scotopic ERG, light aversion, decreased pupil constriction to light, and a 20% loss of optic nerve axons. Daily treatment with both doses of raloxifene for 2 weeks post blast reduced or eliminated the deficits in acuity, contrast sensitivity, light aversion, pupil constriction, and optic nerve axon loss (with the higher dose generally more effective). The B-wave deficit was rescued by the lower dose, but surprisingly not by the higher dose.

Conclusions : Our studies show that raloxifene ameliorates visual system deficits and injury after impact TBI. Our findings provide support for phase-2 efficacy testing in clinical trials, which if effective could lead to the rapid repurposing of raloxifene for treating mild TBI in people.

This is a 2020 ARVO Annual Meeting abstract.