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Review
, 111 (Pt B), 134-41

Photochemical Approaches to Vision Restoration

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Review

Photochemical Approaches to Vision Restoration

Russell N Van Gelder. Vision Res.

Abstract

Photoswitches are traditional pharmacologic agonists, antagonists, or channel blockers that are covalently modified with an azobenzene derivative. Azobenzene undergoes wavelength-dependent isomerization between cis and trans conformation. For some photoswitches, only one of these configurations is biologically active, resulting in light-dependent activation or inhibition of function. Photoswitches that feature a quaternary ammonium coupled to the azobenzene moiety cause light-dependent neuronal depolarization due to blockage of voltage-gated potassium channels. Two photoswitch strategies have been pursued. In the one-component strategy, the photoswitch is applied to native receptors; in the two-component strategy, the photoswitch is combined with virally-mediated expression of a genetically modified receptor, to which the photoswitch may covalently bind. The former approach is simpler but the latter allows precise anatomic targeting of photoswitch activity. Acrylamide-azobenzene-quaternary ammonium (AAQ) is the prototypical first-generation one-component photoswitch. When applied to retinas with outer retinal degeneration, ganglion cell firing occurs in response to blue light, and is abrogated by green light. In vivo, AAQ restored pupillary light responses and behavioral light responses in blind animals. DENAQ is a prototypical second generation one-component photoswitch. It features spontaneous thermal relaxation so cell firing ceases in dark, and features a red-shifted activation spectrum. Interestingly, DENAQ only photoswitches in retinas with outer retinal degeneration. MAG is a photoswitched glutamate analog which covalently binds to a modified ionotropic glutamate receptor, LiGluR. When applied together, MAG and LiGluR also rescue physiologic and behavioral light responses in blind mice. Together, photoswitch compounds offer a potentially useful approach to restoration of vision in outer retinal degeneration.

Keywords: Pharmacology; Photoswitch; Retinal degeneration; Retinal ganglion cells.

Figures

Figure 1
Figure 1
Chemical structure of azobenzene in trans and cis conformations
Figure 2
Figure 2
Structure of maleimide-azobenzene-quarternary ammonium (Mal-Azo-QA, or MAQ), the small molecule photoswitch used in the two-component SPARK channel system. A. Structure of MAQ in trans and cis conformation. B. Schematic of two-component blockade under trans conformation. C. Example of change in cell conductivity with light due to photoswitch activity. From: (Mourot et al., 2013) with permission.
Figure 3
Figure 3
Structure of acrylamide-azobenzene-quarternary ammonium (AAQ)
Figure 4
Figure 4
Reconstitution of retinal ganglion cell firing to rd1/rd1 mouse retina by addition of AAQ, as measured by multi-electrode array (MEA) recording. Upper panel in each is multi-electrode array raster, with each line representing one ganglion cell. Note strong firing under UV light and relative silencing under green light. From: (Polosukhina et al., 2012) with permission.
Figure 5
Figure 5
Structure and absorption spectra of second generation photoswitches. From: (Mourot et al., 2011) with permission.
Figure 6
Figure 6
Conferral of light sensitivity on retinal ganglion cells of rd1/rd1 mice by DENAQ. A. Structure of DENAQ. B. Multi-electrode array recording of rd1/rd1 retina prior to DENAQ administration. C. Recofding from rd1/rd1 retina post-administration of DENAQ. Note cessation of firing in dark. (From: (Tochitsky et al., 2014) with permission)
Figure 7
Figure 7
Structure of maleimide-azobenzene-glutamate (MAG, left) and proposed mechanism of action on ionotropic glutamate receptors. From: (Volgraf et al., 2006) with permission.

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