Neuroprotection: new pharmacological targets

Abstract

Recent research in the field of neuroprotection in glaucoma has focused on the N-methyl-D-aspartate (NMDA) and the a-2 adrenergic receptor systems. Experimental findings have shown that brimonidine (BMD), a specific a-2 adrenoceptor agonist, can protect against loss in mitochondrial membrane potential during oxidative stress, and preserve anterograde axonal transport. Memantine is a selective blocker of the NMDA-type glutamatergic type ion channel. It has unique open channel blocker properties that result in a preferential inhibition of excessive (excitotoxic) neuronal activation by high levels of glutamate without interfering with the channel's normal functions. In a primate model, memantine was neuroprotective as can be seen from its effect on maintaining/ preserving RGCs. Research in Alzheimer's disease has demonstrated that memantine may increase neuronal functionality as well as being protective. Research in a primate glaucoma model shows that memantine protects neurons from shrinking in the lateral geniculate nucleus. Memantine is currently in clinical trials for glaucoma.

Alpha2-adrenergic receptors in spiral ganglion neurons may mediate protective effects of brimonidine and yohimbine against glutamate and hydrogen peroxide toxicity

“…Wheeler et al found that brimonidine could send signals that protect the mitochondria during oxidative stress (Wheeler et al, 2007). In the current study, we demonstrated that brimonidine inhibited H 2 O 2 -induced up-regulation of Bax, Caspase-9 and Caspase-3, increased the expression of Bcl-2, accompanied with up-regulation of a 2b -AR subtype.…”

Effects of advanced glycation end products‐inductor glyoxal and hydrogen peroxide as oxidative stress factors on rat retinal organ cultures and neuroprotection by UK‐14,304

“…The mechanism of UK‐14,304’s protective effect is not yet completely understood. It is known that alpha2‐adrenergic receptor stimulation can activate the anti‐apoptotic phosphatidylinositide 3 kinase/protein kinase B (PI3 kinase/Akt) signal transduction pathway (Wheeler et al. 2007).…”

“…The mechanism of UK-14,304's protective effect is not yet completely understood. It is known that alpha2-adrenergic receptor stimulation can activate the anti-apoptotic phosphatidylinositide 3 kinase/protein kinase B (PI3 kinase/Akt) signal transduction pathway (Wheeler et al 2007). To test which pathway is activated by UK-14,304, we also tested the effect of 304 in the presence of 2-(4-morpholinyl)-8phenyl-4H-1-benzopyran-4-one (Ly 294002), a PI3 kinase inhibitor.…”