Neuroprotection in neurodegenerations of the brain and eye: Lessons from the past and directions for the future

Levin, Leonard A.; Patrick, Christopher J.; Choudry, N B; Sharif, Najam A.; Goldberg, Jeffrey L

doi:10.3389/fneur.2022.964197

Cited by 23 publications

(13 citation statements)

References 128 publications

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“…Alternatively, these observations may parallel the atypical intrinsic hyperactivity observed in degenerating/remodeling rd1 mice retinas, which is thought to arise from remnant photoreceptors and bipolar cells, with activity (and modulation) by horizontal and amacrine cells ( Borowska et al, 2011 ; Haq et al, 2014 ). Sustained activity, even in an aberrant form, has the potential to facilitate retinal neuron regeneration ( Corredor and Goldberg, 2009 ; Lim et al, 2016 ; Levin et al, 2022 ), and we have shown that in zebrafish, surviving photoreceptors facilitate functional recovery following cytotoxic damage ( Sherpa et al, 2014 ). Thirdly, an additional consideration for interpreting the recovery of function within the regenerating zebrafish retina is the restoration and/or remodeling of inhibitory interneuron inputs, including horizontal cells in the outer retina.…”

Section: Discussionmentioning

confidence: 99%

Dynamic functional and structural remodeling during retinal regeneration in zebrafish

Barrett

Mitchell

Meighan

et al. 2022

Front. Mol. Neurosci.

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IntroductionZebrafish regenerate their retinas following damage, resulting in restoration of visual function. Here we evaluate recovery of retinal function through qualitative and quantitative analysis of the electroretinogram (ERG) over time following retinal damage, in correlation to histological features of regenerated retinal tissue.MethodsRetinas of adult zebrafish were lesioned by intravitreal injection of 10 μM (extensive lesion; destroys all neurons) or 2 μM (selective lesion; spares photoreceptors) ouabain. Unlesioned contralateral retinas served as controls. Function of retinal circuitry was analyzed at selected timepoints using ERG recordings from live zebrafish, and whole eyes were processed for histological analyses immediately thereafter.ResultsQualitative and quantitative assessment of waveforms during retinal regeneration revealed dynamic changes that were heterogeneous on an individual level within each sampling time, but still followed common waveform recovery patterns on a per-fish and population-level basis. Early in the regeneration period (13–30 days post injury; DPI), for both lesion types, b-waves were essentially not detected, and unmasked increased apparent amplitudes, implicit times, and half-widths of a-waves (vs. controls). In control recordings, d-waves were not obviously detected, but apparent d-waves (OFF-bipolar responses) from regenerating retinas of several fish became prominent by 30DPI and dominated the post-photoreceptor response (PPR). Beyond 45DPI, b-waves became detectable, and the ratio of apparent d- to b-wave contributions progressively shifted with most, but not all, fish displaying a b-wave dominated PPR. At the latest timepoints (extensive, 90DPI; selective, 80DPI), recordings with measurable b-waves approached a normal waveform (implicit times and half-widths), but amplitudes were not restored to control levels. Histological analyses of the retinas from which ERGs were recorded showed that as regeneration progressed, PKCa + ON-bipolar terminals and parvalbumin + amacrine cell processes became more stereotypically positioned within the deep sublaminae of the INL over recovery time after each lesion type, consistent with the shift in PPR seen in the ERG recordings.DiscussionTaken together, these data suggest that photoreceptor-OFF-bipolar component/connectivity may functionally recover and mature earlier during regeneration compared to the photoreceptor-ON-bipolar component, though the timeframe in which such recovery happens is heterogeneous on a per-fish basis. Collectively our studies suggest gradual restoration of ON-bipolar functional circuitry during retinal regeneration.

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Section: Discussionmentioning

confidence: 99%

Dynamic functional and structural remodeling during retinal regeneration in zebrafish

Barrett

Mitchell

Meighan

et al. 2022

Front. Mol. Neurosci.

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“…Given recent advances in our understanding of the mechanisms of RGC death, a variety of novel approaches for glaucoma neuroprotection are being investigated 9 , 10 . One main challenge for the development of these IOP-independent neuroprotective therapies is the lack of glaucoma progression endpoints that could be tested in clinical trials of relatively short duration in a glaucoma population treated with concomitant IOP-lowering therapies.…”

Section: Introductionmentioning

confidence: 99%

A potential primary endpoint for clinical trials in glaucoma neuroprotection

Moraes

Lane

Wang³

et al. 2023

Sci Rep

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The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period of time (2 years) and the current United States’ Food and Drug Administration (FDA) recommended endpoints for visual field outcomes. If this correlation is strong and highly predictive, clinical trials employing MD slopes as primary endpoints could be employed in neuroprotection clinical trials with shorter duration and help expedite the development of novel IOP-independent therapies. Visual field tests of patients with or suspected glaucoma were selected from an academic institution and evaluated based on two functional progression endpoints: (A) five or more locations worsening by at least 7 dB, and (B) at least five test locations based upon the GCP algorithm. A total of 271 (57.6%) and 278 (59.1%) eyes reached Endpoints A and B, respectively during the follow up period. The median (IQR) MD slope of eyes reaching vs. not reaching Endpoint A and B were −1.19 (−2.00 to −0.41) vs. 0.36 (0.00 to 1.00) dB/year and −1.16 (−1.98 to −0.40) vs. 0.41 (0.02 to 1.03) dB/year, respectively (P < 0.001). It was found that eyes experiencing rapid 24-2 visual field MD slopes over a 2-year period were on average tenfold more likely to reach one of the FDA accepted endpoints during or soon after that period.

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“…The deprivation of these factors resulting from the blockage in retrograde axonal transport to the RGC soma as well as their degradation due to increased ROS levels may trigger apoptosis in RGCs [ 16 , 17 ]. Treatment using these neurotrophic factors have demonstrated protection of RGCs in varying experimental models of injury [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection of Rodent and Human Retinal Ganglion Cells In Vitro/Ex Vivo by the Hybrid Small Molecule SA-2

Pham

Johnson

Rangan

et al. 2022

Cells

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The mechanisms underlying the neuroprotective effects of the hybrid antioxidant-nitric oxide donating compound SA-2 in retinal ganglion cell (RGC) degeneration models were evaluated. The in vitro trophic factor (TF) deprivation model in primary rat RGCs and ex vivo human retinal explants were used to mimic glaucomatous neurodegeneration. Cell survival was assessed after treatment with vehicle or SA-2. In separate experiments, tert-Butyl hydroperoxide (TBHP) and endothelin-3 (ET-3) were used in ex vivo rat retinal explants and primary rat RGCs, respectively, to induce oxidative damage. Mitochondrial and intracellular reactive oxygen species (ROS) were assessed following treatments. In the TF deprivation model, SA-2 treatment produced a significant decrease in apoptotic and dead cell counts in primary RGCs and a significant increase in RGC survival in ex vivo human retinal explants. In the oxidative stress-induced models, a significant decrease in the production of ROS was observed in the SA-2-treated group compared to the vehicle-treated group. Compound SA-2 was neuroprotective against various glaucomatous insults in the rat and human RGCs by reducing apoptosis and decreasing ROS levels. Amelioration of mitochondrial and cellular oxidative stress by SA-2 may be a potential therapeutic strategy for preventing neurodegeneration in glaucomatous RGCs.

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Neuroprotection in neurodegenerations of the brain and eye: Lessons from the past and directions for the future

Cited by 23 publications

References 128 publications

Dynamic functional and structural remodeling during retinal regeneration in zebrafish

Dynamic functional and structural remodeling during retinal regeneration in zebrafish

A potential primary endpoint for clinical trials in glaucoma neuroprotection

Neuroprotection of Rodent and Human Retinal Ganglion Cells In Vitro/Ex Vivo by the Hybrid Small Molecule SA-2

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