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      Effect of Steroidal and Non-Steroidal Drugs on the Microglia Activation Pattern and the Course of Degeneration in the Retinal Degeneration Slow Mouse

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          Background: In hereditary retinal degeneration, microglia cells become activated, migrate through the outer nuclear layer (ONL) and accumulate in the subretinal space. Although this inflammatory process is not likely to be responsible for the onset of photoreceptor apoptosis, cytotoxic substances secreted by activated microglia could potentially accelerate and perpetuate the degenerative process. Anti-inflammatory drugs have been shown to modulate the microglia response in neurodegenerative disorders and potentially ameliorate the disease progression in various animal model systems. In this study we wanted to test the impact of the most commonly used anti-inflammatory drugs (acetylsalicylate and prednisolone) on the microglia activation pattern, the rate of caspase-3-dependent photoreceptor apoptosis and the course of the degeneration in the retinal degeneration slow (rds) mouse retina. Methods: 169 pigmented rds mice and 30 CBA wild-type mice were used for this study. The treatment groups were injected daily with either acetylsalicylate (200 mg/kg) or prednisolone (2 mg/kg) i.p. from day 0 up to 3 months. Animals were sacrificed at days 10, 14, 16, 18, 20, 30, 40, 60 and 90. Cryoprotected frozen sections were immunostained with F4/80 and cleaved caspase-3 antibodies. The main outcome measures were the total microglia count in the subretinal space, the total cleaved caspase-3-positive cells in the ONL and the averaged number of photoreceptor rows in the midperipheral retina. Results: Neither acetylsalicylate nor prednisolone reduced subretinal microglia accumulation in the rds mouse degeneration model. Moreover, they aggravated migration and accumulation in the early time course. The apoptotic cascade started earlier and was more pronounced in both treatment groups compared to the control group. The pace of retinal degeneration was not reduced in the treatment groups compared to the untreated control. In contrast, acetylsalicylate did significantly accelerate the photoreceptor cell degeneration in comparison to the prednisolone (p < 0.001) and to the control group (p < 0.001). Conclusions: Acetylsalicylate and prednisolone do not decrease the microglia response in the rds mouse and are not neuroprotective. More research is needed to clarify the molecular mechanisms which lead to photoreceptor cell death and to elucidate the complex role of microglia in inherited retinal degeneration.

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          Most cited references 45

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          Reactive microgliosis.

          Damage to the central nervous system (CNS) elicits the activation of both astrocytes and microglia. This review is focused on the principal features that characterize the activation of microglia after CNS injury. It provides a critical discussion of concepts regarding microglial biology that include the relationship between microglia and macrophages, as well as the role of microglia as immunocompetent cells of the CNS. Mechanistic and functional aspects of microgliosis are discussed primarily in the context of microglial neuronal interactions. The controversial issue of whether reactive microgliosis is a beneficial or a harmful process is addressed, and a resolution of this dilemma is offered by suggesting different interpretations of the term 'activated microglia' depending on its usage during in vivo or in vitro experimentation.
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            Microglia as neuroprotective, immunocompetent cells of the CNS.

             W Streit (2002)
            The role of glial cells is to support and sustain proper neuronal function and microglia are no exception to this. This viewpoint article emphasizes the fundamental interdependence of microglia and neurons and takes a look at the possibility of what could happen if microglial cells became dysfunctional as a result of aging, genetics, or epigenetics. Could microglial senescence be a factor in the pathogenesis of Alzheimer's and other neurodegenerative diseases? The cautious answer to that question is 'yes'. Future studies along these lines may provide novel insights into microglial involvement in neurodegenerative disease pathogenesis. Copyright 2002 Wiley-Liss, Inc.
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              Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration.

              Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E(2) have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E(2) synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNKc-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                April 2005
                20 May 2005
                : 37
                : 2
                : 72-82
                aUniversity Eye Clinic, Bern, Switzerland; bInstitute of Ophthalmology, London, UK, and cUniversity Eye Clinic, Leipzig, Germany
                84248 Ophthalmic Res 2005;37:72–82
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 9, Tables: 3, References: 61, Pages: 11
                Original Paper


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