Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier.

BACKGROUND: The presence of calcitonin gene-related peptide and its receptors in multiple brain areas and peripheral tissues previously implicated in migraine initiation and its many associated symptoms raises the possibility that humanized monoclonal anti-calcitonin gene-related peptide antibodies (CGRP-mAbs) can prevent migraine by modulating neuronal behavior inside and outside the brain. Critical to our ability to conduct a fair discussion over the mechanisms of action of CGRP-mAbs in migraine prevention is data generation that determines which of the many possible peripheral and central sites are accessible to these antibodies - a question raised frequently due to their large size. MATERIAL AND METHODS: Rats with uncompromised and compromised blood-brain barrier (BBB) were injected with Alexa Fluor 594-conjugated fremanezumab (Frema594), sacrificed 4 h or 7 d later, and relevant tissues were examined for the presence of Frema594. RESULTS: In rats with uncompromised BBB, Frema594 was similarly observed at 4 h and 7 d in the dura, dural blood vessels, trigeminal ganglion, C2 dorsal root ganglion, the parasympathetic sphenopalatine ganglion and the sympathetic superior cervical ganglion but not in the spinal trigeminal nucleus, thalamus, hypothalamus or cortex. In rats with compromised BBB, Frema594 was detected in the cortex (100 µm surrounding the compromised BBB site) 4 h but not 7 d after injections. DISCUSSION: Our inability to detect fluorescent (CGRP-mAbs) in the brain supports the conclusion that CGRP-mAbs prevent the headache phase of migraine by acting mostly, if not exclusively, outside the brain as the amount of CGRP-mAbs that enters the brain (if any) is too small to be physiologically meaningful.

Choroidal ganglion cell plexus and retinal vasculature in monkeys with laser-induced glaucoma.

The choroid of primates possesses an elaborate nitrergic nerve fiber plexus containing a great number of ganglion cells. Postganglionic nerve fibers innervate mainly the choroidal vasculature. In addition, the choroid contains an elastic muscular system closely associated to the vasculature. The goal of the present investigation was to analyze how sustained IOP elevation would affect the choroidal vasculature with its specialized innervation and the adjacent retina. For this purpose the posterior eye segment of 15 rhesus monkeys which after laser coagulation of the trabecular meshwork developed elevated IOP up to 4 years were studied using immunohistochemical and histochemical methods, and scanning electron microscopy of corrosion casts. The most striking finding was a significant reduction of choroidal thickness and loss of choroidal ganglion cells and nerve fibers, especially in the central portion of the choroid. Corrosion casts of the choroidal vasculature showed a slight decrease in capillary density and a decrease in length of the arterioles in glaucomatous eyes. Whole mount preparations of the retina stained for NADPH diaphorase revealed a significant reduction in positively stained amacrine cells, reduction in diameter of arterioles and changes in the staining pattern of the retinal vasculature, particularly in the perimacular region.