Yoshiko Takano

Study of pharmacological effects of nilvadipine on RCS rat retinal degeneration by microarray analysis.

In our recent study, we found that the Ca(2+) antagonist, nilvadipine caused significant preservation of photoreceptor cells in The Royal College of Surgeons (RCS) rats [Invest. Ophthalmol. Vis. Sci. 43 (2002) 919]. Here, to elucidate the mechanisms of nilvadipine-induced effects we analyzed altered gene expression of 1101 genes commonly expressed in rodent by DNA microarray analysis in the retinas of nilvadipine-treated and untreated RCS rats and SD rat. In the total number of genes, the expression of 30 genes was altered upon administration of nilvadipine to RCS rats, including several genes related to the apoptotic pathway and other mechanisms. Remarkably, neurotrophic factors, FGF-2 and Arc, known to suppress the apoptosis in the central nervous system, were up-regulated. These changes were also confirmed by real-time quantitative (Taqman) RT-PCR and Western blot analysis. Therefore, our present data suggested that administration of nilvadipine to RCS rats increases the expression of endogenous FGF-2 and Arc in retina, and potentially has a protective effect against retinal degeneration.

Acute zonal occult outer retinopathy in the fellow eye 5 years after presentation of punctate inner choroidopathy

BackgroundThere has been argument about the relationship between posterior inner choroidopathy (PIC) and acute zonal occult outer retinopathy (AZOOR).MethodCase study.ResultsA 26-year-old woman was diagnosed as having PIC in the right eye in 1998. Multiple yellow–white lesions in the inner choroid and retina were found in the posterior pole of her right eye and were treated with corticosteroid therapy. In 2003, she was referred to us complaining of visual field defect in the left eye. By means of electroretinographic and static perimetric analyses, she was diagnosed as having AZOOR in the left eye.ConclusionThis case presents indirect evidence that PIC and AZOOR may have some common etiologic or pathogenic background.

Low expression of rhodopsin kinase in pineal gland in Royal College of Surgeons rat

The Royal College of Surgeons (RCS) rat has been extensively characterized as a model for inherited retinal dystrophy such as retinitis pigmentosa. We have found that significantly low levels of expression of rhodopsin kinase (RK) and aA-crystallin may be involved in the pathogenesis of retinal degeneration in the RCS rat (Invest Ophthalmol Vis Sci. 1999,40:2788-2794). In the present study, we examined the expression of photoreceptor specific proteins in the pineal gland (PG) including rhodopsin kinase (RK), arrestin and recoverin, which are known to be commonly present in both photoreceptor and PG, in order to elucidate the pathological relationship between retina and PG during retinal degeneration. Among these proteins, RK expression was significantly decreased with advancing age (3–5 weeks old) in RCS rat. However, in contrast, arrestin expression in RCS PG was comparable with control PG and no expressions of recoverin and other G-protein coupled receptor kinases (GRKs 2, 5 and 6) were detected in RCS PG during 3–5 weeks of age. By administration of nilvadipine, an effective Ca 2+ antagonist that was shown to preserve RCS retinal degeneration, RK expression was significantly enhanced.

Effects of calcium channel blockers on retinal morphology and function of rd mouse

Retinitis pigmentosa (RP) is a disease of inherited retinal degeneration characterized by nyctalopia, ring scotoma, and bone-spicule pigmentation of the retina. So far, no effective therapy has been available for RP. Several animal models with inherited retinal degeneration have been studied in order to elucidate the molecular pathology of RP, and to design an effective therapy for it. Frasson et al. [1] recently reported rod photoreceptor rescue by d-cis-diltiazem, a Ca2+ channel blocker in a different animal model of RP, rd mouse, in which the gene encoding cyclic guanosine monophosphate phosphodiesterase is affected. In addition, our group found that systemic administration of another type of Ca2+ channel blocker, nilvadipine, caused significant preservation of retinal morphology and function in Royal College of Surgeons (RCS) retinal degeneration [2]. These data suggest that the regulation of intracellular Ca2+ levels may be a possible therapy to prevent progressive retinal degeneration in RP and its animal models. So far, many Ca2+ channel blockers have been used in our clinical practice. Therefore, it seems very important to know which Ca2+ channel blocker is the most effective for retinal degeneration in RP.

Pharmacological Aspects of Nilvadipine-Induced Preservation of Retinal Degeneration in RCS Rat Analyzed by mRNA Profiling Assay

In our study, we found that the Ca2+ antagonist nilvadipine was beneficial for the preservation of photoreceptor cells in The Royal College of Surgeons (RCS) rats. Here, in order to elucidate mechanisms of its nilvadipine-induced photoreceptor preservation, we analyzed altered gene expressions of the retina in RCS rats administered nilvadipine by mRNA profiling assay. Total RNA isolated from the retina with or without nilvadipine was converted into cDNA. Utilizing DNA microarray analysis methods, we compared the overall expression patterns for 1101 genes that were commonly expressed in rodent. Of the total genes, the expression of less than 30 genes was altered significantly including that of several genes involved in cellular regulation. On the basis of these data, it is suggested that microarray analysis is a useful tool and applicable for studying the pharmacological effects of several drugs including Ca2+ channel blockers to retinal degeneration.

Nilvadipine, a Ca2+ Antagonist, Effectively Preserves Photoreceptor Functions in Royal College of Surgeons Rat

The Royal College of Surgeons (RCS) rat is the most extensively studied animal model for understanding the molecular pathology of inherited retinal degeneration, such as retinitis pigmentosa (RP). We recently found lower levels of rhodopsin kinase expression in RCS rats as compared with control rats, leading us to speculate that misregulation of the phototransduction pathways by the low levels of rhodopsin phosphorylation might be a critical step causing the retinal degeneration. Here, effects of suppression of recoverin-dependent inhibition of rhodopsin phosphorylation on the retinal degeneration in RCS rats by lowering intracellular Ca2+ levels by intraperitoneal administration of nilvadipine, a calcium antagonist, and retinal functions and morphology were analyzed. We found that systemic administration of nilvadipine caused remarkable preservation of photoreceptor functions, electroretinogram responses, and retinal morphology in RCS rats during the initial stage of the retinal degeneration. On the basis of these data, it was strongly suggested that nilvadipine is beneficial for the preservation of photoreceptor cells in RCS rats and can potentially be used to treat some RP patients.

Cancer-Associated Retinopathy (CAR) is Effectively Treated by Ca2+ Antagonist Administration

Cancer-associated retinopathy (CAR) is a paraneoplastic ocular manifestation in which recoverin acts as an autoantigen recognized by sera from patients. Recently, we have found that CAR-like retinal dysfunction was produced by intravitreous administration of antirecoverin antibody in Lewis rat eyes. In the present study, nilvadipine, a Ca2+ antagonist recently found effective as a drug for inherited retinal degeneration, was evaluated for its effectiveness on the retinal degenerations in CAR using these models. Under medication with nilvadipine, the functional and morphological properties of the retinas were evaluated functionally and morphologically following antirecoverin antibody intravitreous injection into Lewis rats’ eyes (six rats, 12 eyes in each experimental condition were used). Administration of nilvadipine to the antirecoverin antibody-treated rats caused significant improvement of the deterioration of ERG and normalization of rhodopsin phosphorylation. The present data indicated that antirecoverin antibody-induced retinal dysfunction can be effectively treated by systemic administration of nilvadipine.

Aberrantly Expressed Recoverin in Tumor Tissues from Gastric Cancer Patients

A variety of neurological symptoms characterizing paraneoplastic syndromes, such as Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar degeneration, are well known to be associated with malignant neoplasms even though there is no evidence of nervous system invasion [1]. The possible pathogenesis is an autoimmune reaction toward aberrantly expressed neuron-specific antigens in cancer cells that presumably triggers immunological responses and causes neuronal cell degeneration. Cancer-associated retinopathy (CAR) has been identified as an ocular manifestation of paraneoplastic syndrome [2]. CAR is frequently found in patients with small cell carcinoma of the lung and other malignancies, and is clinically characterized with retinitis pigmentosa-like retinal degeneration including photopsia, progressive visual loss with a ring scotoma, attenuated retinal arterioles, and abnormalities of the a-and b-waves of an electroretinogram (ERG) [3]. Histopathology has shown primarily a loss of photoreceptor cells [2]. In terms of CAR autoantigen, a photoreceptor-specific, 26-kDa calcium-binding protein called recoverin [4] and other retinal antigens were identified. Recoverin is known to play an important role in light and dark adaptation by regulating rhodopsin phosphorylation and dephosphorylation in a calcium-dependent manner [5]. Alternatively, recoverin is also known to be a highly immunogenic molecule and to experimentally cause uveoretinitis in rat by its immunization [6]. A mechanism that has been postulated for the apoptotic cell death of photoreceptor cells observed in CAR is that antirecoverin antibody generated by unknown mechanisms in some cancer patients penetrates into the photoreceptor cells via the peripheral circulation and causes misregulation of the phototransduction pathway by blocking recoverin function [7].