C. Stephen Foster, MD

Disclosures

July 20, 2012

Promising Neuroprotective Effects of Brimonidine

Further to the matter of neuroprotection, brimonidine was the subject of several presentations.

Calixto and colleagues[3] reported on the effect of brimonidine tartrate on circulating retinal spreading depression. Spread depression was originally described in the rabbit cerebral cortex by Leão in 1947[4] and first identified on the retina by Gouras[5] in 1958.

Spread depression is widely associated with neuronal damage, and it can also be seen in the retina as a propagating depolarization wave. While it spreads through retina, electrical and intrinsic optical signs can be measured. Circulating spread depression is a unique model in which once the first stimulus is done, it continuously propagates through the tissue.

Calixto and colleagues performed experiments on fragments of retinal preparations of White Leghorn chicks from 3 to 8 days after hatching. Fragments of retina were transferred to a chamber and infused with modified Ringer solution driven by a peristaltic pump to maintain flow of the solution at a rate of 0.8-0.85 mL/min. The temperature in the chamber was set at 30°C by means of a thermostatic bath. The composition of the Ringer solution (in mM) was NaCl 100.0, KCl 6.0, CaCl2 1.0, MgSO4 1.0, NaHPO4 1.0, NaHCO3 30.0, and glucose 20.0.

The presence or absence of spread depression was detected by recording its concomitant slow-voltage variations through 2 pore electrodes connected to a Grass polygraph. All experiments started with a control procedure. First, the retina infused with Ringer solution was mechanically stimulated by a sharpened tungsten wire, triggering spread depression. After 9 minutes, the infusion was changed to Ringer solution containing 0.1% brimonidine tartrate (0.1% RS/BT) for 9 minutes. After that, the infusion was once more changed for a Ringer solution containing 0.2% brimonidine tartrate (0.2% RS/BT).

The data demonstrated that 0.1% RS/BT reduces the amplitude of the negative potential shift from 25.89 ± 2.66 mV to 21.44 ± 2.11 mV. With 0.2% RS/BT, spread depression is blocked. The interval between 2 passages through the same electrode was increased from 59.17 ± 0.95 seconds to 78.78 ± 2.26 seconds (0.1% RS/BT).

Although the main effect of the brimonidine tartrate pathway is still not well understood, it is clear that it is powerful. The recent association of spread depression with many traumatic disorders of the central nervous tissue leads us to wonder how brimonidine tartrate blocks spread depression. Possibly, it acts as a neuroprotective drug.

Ameliorating Ischemia/Reperfusion Injury

Abcouwer and colleagues[6] also examined the ability of brimonidine to protect neurons from apoptotic cell death. Ischemic retinal diseases, such as retinal vein and arterial occlusions, have limited therapeutic options. Retinal ischemia/reperfusion (IR) is an acute model of retinal degeneration, demonstrating neuronal death, vascular hyperpermeability, microgliosis, and macrophage infiltration. The alpha2-adrenergic receptor (alpha2-AR) agonist brimonidine has demonstrated neuroprotective potential. These investigators hypothesized that alpha2-AR agonists would prevent IR-induced neuronal degeneration and vascular permeability, resulting in diminished innate and inflammatory immune responses.

Rats were pretreated with intraperitoneal injection of the alpha2-AR agonists brimonidine and guanfacine before IR. Retinas were made ischemic by transient elevation of intraocular pressure for 45 minutes and reperfused for up to 48 hours. Cell death was evaluated by TUNEL assay and by measurement of internucleosomal DNA cleavage. Extravascular albumin was measured using the Evan blue dye technique. Microgliosis and monocyte populations were evaluated by flow cytometry of enzymatically dissociated retinal cells. Global changes in whole retina gene expression were identified in repeated microarray analyses, with selective confirmation by quantitative reverse-transcriptase polymerase chain reaction. Retinal monocytes were enriched by density gradient centrifugation before analysis of messenger RNA expression by quantitative reverse-transcriptase polymerase chain reaction.

In addition to neuronal death and vascular hyperpermeability, IR significantly (P ≤ .01) increased CD45 expression and granularity of microglia, indicating activation and phagocytic activity. IR also significantly (P ≤ .01) increased the number of macrophages, including cells with high expression of major histocompatibility complex class II, indicating an inflammatory antigen-presenting phenotype.

Pretreatment with alpha2-AR agonists greatly (P ≤ .01) diminished cell death, albumin leakage, microglial activation, and macrophage accumulation in response to IR. Pretreatment also significantly (P ≤ .50) inhibited most gene expression changes caused by IR. Twenty-four response-inhibited genes were validated, and 22 of these were highly expressed by enriched retinal monocytes.

Abcouwer and associates concluded that pretreatment with alpha2-AR agonists effectively prevented neuronal, vascular, and innate immune responses to IR injury. This class of drugs may represent an effective means to prevent ischemic damage and treat retinal vein and arterial occlusions.

Neuroprotection: Our Best Hope Right Now?

Stem cell and nerve growth factor therapies may hold the ultimate promise for nerve regeneration in patients with vision loss secondary to neurodegenerative diseases, including glaucoma. But until such therapy is a reality, our current best hope for patients who have progressive glaucomatous optic neuropathy despite normal or subnormal intraocular pressure is neuroprotection. As the research described above makes clear, neuroprotection treatment strategies may be at our doorstep; thus, this is a research area that deserves our undivided attention in the coming years.

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