Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone

Rojas, Julio C.; Saavedra, J. A.; González-Lima, Francisco

doi:10.1016/j.brainres.2008.04.001

Cited by 36 publications

(42 citation statements)

References 41 publications

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“…In fact, memantine reduced the oxidative damage to proteins in cortex and hippocampus in aged rats (Pietá Dias et al 2007). Moreover, memantine was neuroprotective against rotenone, which an inhibitor of mitochondrial complex I (Rojas et al 2008) and reduced ROS and lipid peroxidation induced by organophosphate in rat brain (Zaja-Milatovic et al 2009). Memantine also prevent the deleterious effects of mitochondrial dysfunction induced by complex II inhibitors, malonate and 3-nitropropionic acid (Schulz et al 1996;Karanian et al 2006;Volbracht et al 2006).…”

Section: Discussionmentioning

confidence: 97%

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

et al. 2011

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Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.

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Section: Discussionmentioning

confidence: 97%

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

et al. 2011

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“…Surgical procedures were similar to those as in our previous reports except that rats were used instead of mice (Zhang et al 2002(Zhang et al , 2006aRojas et al 2008a). In brief, subjects were anesthetized with 2% isoflurane (Baxter, Deerfield, IL) using an E-Z anesthesia vaporizer system (Euthanex, Corp, Palmer, PA).…”

Section: Surgeriesmentioning

confidence: 98%

“…The specific doses of rotenone and MB chosen were based on our previous studies indicating morphological retinal toxicity and neuroprotection, respectively (Zhang et al 2002(Zhang et al , 2006aRojas et al 2008a). The vitreous bodies of both eyes of each subject were injected with either: 1) Control group: the vehicle dimethylsulfoxide (DMSO) only as control (n = 5), 2) Rotenone group: 200 lg/kg rotenone in DMSO (n = 5), 3) Rotenone plus MB group: 200 lg/kg rotenone in the vehicle DMSO, plus 70 lg/kg MB (n = 5), Fig.…”

Section: Drug Treatmentsmentioning

confidence: 99%

Methylene Blue Provides Behavioral and Metabolic Neuroprotection Against Optic Neuropathy

et al. 2009

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Methylene blue (MB) is a diaminophenothiazine with potent antioxidant and unique redox properties that prevent morphologic degenerative changes in the mouse retina induced by rotenone, a specific mitochondrial complex I inhibitor. This study evaluated pigmented rats to determine whether MB's neuroprotective effects against rotenone-mediated retinal neurotoxicity have functional relevance and whether these effects are mediated by an improvement in neuronal energy metabolism in vivo. Visual function was behaviorally assessed by determining differences in the illuminance sensitivity threshold pre- and post-bilateral intravitreal injection of rotenone (200 microg/kg) or rotenone plus MB (70 microg/kg). Retinal degeneration was morphologically studied using unbiased stereological tools. Changes in histochemically determined cytochrome oxidase activity in the visual pathway were used to evaluate the impact of treatments on neuronal energy metabolism. Rotenone induced a 1.4 log unit increase in the illumination threshold compared to baseline, as well as a 32% decrease in ganglion cell layer cell (GCL) density, and a 56% decrease in GCL layer + nerve fiber layer thickness. Co-administration of MB prevented the changes in visual function and the retinal histopathology. Furthermore, rotenone induced a functional deafferentation of the visual system, as revealed by decreases in the metabolic activity of the retina, superior colliculus, and visual cortex. These metabolic changes were also prevented by MB. The results provided the first demonstration of MB's behavioral and metabolic neuroprotection against optic neuropathy, and implicate MB as a candidate neuroprotective agent with metabolic-enhancing properties that may be used in the treatment of neurodegenerative diseases associated with mitochondrial dysfunction.

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“…-ATPase due to energy deprivation and the subsequent accumulation of sodium in the intracellular space may facilitate sodium-dependent reversal of GlyT-1 operation. Thus, elevation of intracellular sodium concentrations following rotenone administration may also be a factor in inducing retinal degeneration by this neurotoxin [62].…”

Section: Alteration Of Intracellular Sodium Levels: Effects On [ 3 H]mentioning

confidence: 99%

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

et al. 2015

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Rat posterior eyecups containing the retina were prepared, loaded with [(3)H]glycine and superfused in order to determine its release originated from glycinergic amacrine cells and/or glial cells. Deprivation of oxygen and glucose from the Krebs-bicarbonate buffer used for superfusion evoked a marked increase of [(3)H]glycine release, an effect that was found to be external Ca(2+)-independent. Whereas oxygen and glucose deprivation increased [(3)H]glycine release, its uptake was reduced suggesting that energy deficiency shifts glycine transporter type-1 operation from normal to reverse mode. The increased release of [(3)H]glycine evoked by oxygen and glucose deprivation was suspended by addition of the non-competitive glycine transporter type-1 inhibitor NFPS and the competitive inhibitor ACPPB further suggesting the involvement of this transporter in the mediation of [(3)H]glycine release. Oxygen and glucose deprivation also evoked [(3)H]glutamate release from rat retina and the concomitantly occurring release of the NMDA receptor agonist glutamate and the coagonist glycine makes NMDA receptor pathological overstimulation possible in hypoxic conditions. [(3)H]Glutamate release was suspended by addition of the excitatory amino acid transporter inhibitor TBOA. Sarcosine, a substrate inhibitor of glycine transporter type-1, also increased [(3)H]glycine release probably by heteroexchange shifting transporter operation into reverse mode. This effect of sarcosine was also external Ca(2+)-independent and could be suspended by NFPS. Energy deficiency in retina induced by ouabain, an inhibitor of the Na(+)-K(+)-dependent ATPase, and by rotenone, a mitochondrial complex I inhibitor added with the glycolytic inhibitor 2-deoxy-D-glucose, led to increase of retinal [(3)H]glycine efflux. These effects of ouabain and rotenone/2-deoxy-D-glucose could also be blocked by NFPS pointed to the preferential reverse mode operation of glycine transporter type-1 as a consequence of impaired cellular energy homeostasis. Immunohistochemical studies revealed that glycine transporter type-1, of which reverse mode operation assures [(3)H]glycine release, is expressed in amacrine cells in the inner nuclear and plexiform layers of the retina and also in Müller macroglia cells. We conclude that disruption of the balanced normal/reverse mode operation of glycine transporter type-1 is likely a significant factor contributing to neurotoxic processes of the retina. The possibility to inhibit glycine transporter type-1 mediated glycine efflux by drugs more potently than glycine uptake might offer some therapeutic potential for the treatment of various neurodegenerative disorders of the retina.

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Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone

Cited by 36 publications

References 41 publications

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

Methylene Blue Provides Behavioral and Metabolic Neuroprotection Against Optic Neuropathy

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

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