Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse

Takano, Yoshiko; Ohguro, Hiroshi; Dezawa, Mari; Ishikawa, Hiroto; Yamazaki, Hitoshi; Ohguro, Ikuyo; Mamiya, Kazuhisa; Metoki, Tomomi; Ishikawa, Futoshi; Nakazawa, Makoto

doi:10.1016/j.bbrc.2003.12.034

Cited by 71 publications

(61 citation statements)

References 35 publications

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“…This stimulates an influx of calcium. The elevation of internal Ca 2ϩ may be the apoptotic trigger but this idea has not been rigorously tested and data evaluating this possibility are inconsistent (Frasson et al, 1999;Bush et al, 2000;Pearce-Kelling et al, 2001;Pawlyk et al, 2002;Yamazaki et al, 2002;Takano et al, 2004;Vallazza-Deschamps et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

Stearns¹,

Evangelista²,

Fadool³

et al. 2007

J. Neurosci.

110

129

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Photoreceptor degeneration is a common cause of inherited blindness worldwide. We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors caused by a mutation in the cone phosphodiesterase c ( pde6c) gene, a key regulatory component in cone phototransduction. Some rods also degenerate, primarily in areas with a low density of rods. Rod photoreceptors in areas of the retina that always have a high density of rods are protected from degeneration. Our findings demonstrate that, analogous to what happens to rod photoreceptors in the rd1 mouse model, loss of cone phosphodiesterase leads to rapid degeneration of cone photoreceptors. Furthermore, we propose that cell density plays a key role in determining whether rod photoreceptors degenerate as a secondary consequence to cone degeneration. Our zebrafish mutant serves as a model for developing therapeutic treatments for photoreceptor degeneration in humans.

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Section: Discussionmentioning

confidence: 99%

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

Stearns¹,

Evangelista²,

Fadool³

et al. 2007

J. Neurosci.

110

129

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“…However, in the rd1 retina, the light-dependent regulation of CaMKII activation as well as phosducin phosphorylation was found to be impaired. There is consensus on increased Ca 2ϩ levels in rd1 photoreceptors (7,8,13,14), and high Ca 2ϩ has likely contributed to the constitutive activation of CaMKII, which thus in turn could have contributed to the increased phosducin phosphorylation in rd1 independently of light conditions. However, it should be noted that an involvement of other Ca 2ϩ -dependent kinases cannot be ruled out in this context.…”

Section: Discussionmentioning

confidence: 99%

“…Increased intracellular Ca 2ϩ per se has been correlated with rod cell death (8,9), and it is reasonable that uncontrolled Ca 2ϩ influx into rd1 rods triggers apoptosis, which characterizes the photoreceptor degeneration in this model (10 -12). In accordance, Ca 2ϩ channel blockers have been shown to rescue rd1 photoreceptors (13,14). However, although a consensus on the role of Ca 2ϩ as initiator of degeneration in the rd1 retina may exist, the cellular steps subsequent to this remain unresolved, leading for instance to conflicting views on whether caspase cascades underlie the execution of apoptosis.…”

mentioning

confidence: 95%

Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments

Hauck¹,

Ekström

Ahuja-Jensen

et al. 2006

Molecular & Cellular Proteomics

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Retinitis pigmentosa comprises a heterogeneous group of incurable progressive blinding diseases with unknown pathogenic mechanisms. The retinal degeneration 1 (rd1) mouse is a retinitis pigmentosa model that carries a mutation in a rod photoreceptor-specific phosphodiesterase gene, leading to rapid degeneration of these cells. Elucidation of the molecular differences between rd1 and healthy retinae is crucial for explaining this degeneration and could assist in suggesting novel therapies. Here we used high resolution proteomics to compare the proteomes of the rd1 mouse retina and its congenic, wildtype counterpart at postnatal day 11 when photoreceptor death is profound. Over 3000 protein spots were consistently resolved by two-dimensional gel electrophoresis and subjected to a rigorous filtering procedure involving computer-based spot analyses. Five proteins were accepted as being differentially expressed in the rd1 model and subsequently identified by mass spectrometry. The difference in one such protein, phosducin, related to an altered modification pattern in the rd1 retina rather than to changed expression levels. Additional experiments showed phosducin in healthy retinae to be highly phosphorylated in the dark-but not in the light-adapted phase. In contrast, rd1 phosducin was highly phosphorylated irrespective of light status, indicating a dysfunctional rd1 light/dark response. The increased rd1 phosducin phosphorylation coincided with increased activation of calcium/calmodulin-activated protein kinase II, which is known to utilize phosducin as a substrate. Given the increased rod calcium levels present in the rd1 mutation, calcium-evoked overactivation of this kinase may be an early and long sought for step in events leading to photoreceptor degeneration in the rd1 mouse. Molecular & Cellular Proteomics 5:324 -336, 2006.

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“…Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5,6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7)(8)(9).…”

mentioning

confidence: 99%

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2 + APC + oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.M ultiple sclerosis (MS) is the most prevalent neurological disease of the CNS in young adults and is characterized by inflammation, demyelination, and axonal pathology (1) that result in multiple neurological and cognitive deficits (1-3). Intensive MS research studies have investigated modulating the immune system (4). Common therapeutic strategies are effective in slowing disease progression and attenuating the symptoms, but they cannot cure the disease. The option of preventing neurodegeneration early on would be a valuable addendum to customary treatment (4). Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5, 6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7-9). Current research trials are examining its effects on brain injury, epilepsy, cognitive performance, and behavioral effects (6,7,10,11). Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10, 12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6). So far, nimodipine-mediated effects in the CNS have been claimed to result mainly from the modulation of neuronal activity, and studies on the potential effects of nimodipine on (micro)glia have not yet been conduct...

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Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse

Cited by 71 publications

References 35 publications

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

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