Vigabatrin-Induced Retinal Functional Alterations and Second-Order Neuron Plasticity in C57BL/6J Mice

Abstract

PURPOSE. Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results. METHODS. We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry. RESULTS. No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain. CONCLUSIONS. No evidence of significant retinal thinning or ERG a-or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

“…Since vigabatrin increases GABA levels overall [ 150 ], this GABA increase in the retinal area leads to unnecessary and prolonged retinal cellular membrane depolarization, followed by Cl - , Na + , and water flux, thereby causing homeostatic imbalance and cellular death [ 151 ]. In an animal study conducted in 2020, the relationship between vigabatrin and GABA concentrations in the retina and retinal toxicity of vigabatrin was affirmed [ 152 ]. The frequency and severity of the visual field loss caused by vigabatrin have ensured its prescription to only be made to epileptic patients if the anti-seizure benefits outweighed the vision risks.…”

Transcriptome analysis in mice treated with vigabatrin identifies dysregulation of genes associated with retinal signaling circuitry

“…Brain derived neurotrophic factor (BDNF; a member of the neurotrophin growth factor family) plays a significant role in axonal protection, retinal ganglia cell integrity, and stabilization of growing retinal axons via BDNF/nitric oxide signaling (Ernst et al 2000). Dysregulation of Bdnf levels are consistent with the significant extension of dendrites into the retinal outer nuclear layer that we recently reported (Chan et al, 2020), but more detailed studies are needed to examine the potential link(s) between Bdnf and RNFL. Sox 9 plays an important role in the development of the vertebrate eye (Huang et al, 2013).…”

“…Upregulation of Sox 9 (Table 1) may represent a protective response to VGB intervention in retinal Müller cell. Moreover, Sox 9 upregulation may have correlated with extensive rod and cone bipolar, and horizontal cell remodeling, that we observed with VGB administration (Chan et al, 2020), hypotheses which require further investigation. SNARE (SNAP receptors) represent protein complexes that mediate vesicle fusion in mammals.…”

“…Continuous administration of VGB to mice resulted in significant dysregulation of five genes: Gb5 (guanine nucleotide binding protein (G protein), beta 5), Crh (corticotropin releasing hormone), Bdnf (brain derived neurotrophic factor), Sox 9 (SRY-box containing gene 9), and Cplx3 (complexin 3). We previously demonstrated that 140 mg/kg/d VGB, administered to adult mice resulted in GABA accumulation in eye exceeding that of brain (Walters et al 2019;Chan et al, 2020). The relationship of these five genes with GABA, GABAergic receptors, or intracellular signaling has been previously established (Colmers et al 2018;Puller et al 2014;Maqsood et al 2016).…”

Outer Retinal Cell Replacement: Putting the Pieces Together

“…Although there is evidence of some efficacy following hPSC-PRP delivery even in end-stage retinal degeneration—suggesting that host inner retinal circuitry remains viable for a time—the exact window of opportunity for effective cell replacement is currently unknown. 34 , 219 Treatments being studied seek to modulate a variety of naturally occurring processes that may act as barriers to donor PR integration in the degenerate outer retina, including glial scarring, 220 interneuron plasticity, 221 and neurite outgrowth, 222 which may in turn help create a more donor cell-receptive environment. Basic discovery research to better understand the molecular mechanisms involved in retinal circuit assembly, disassembly, and re-assembly will also be essential to address host-centered barriers to neuronal replacement.…”