Methylene Blue Prevents Neurodegeneration Caused by Rotenone in the Retina

Overview

Journal Neurotox Res

Publisher Springer

Specialty Neurology

Date 2006 Feb 9

PMID 16464752

Citations 62

Authors

Xian Zhang

Julio C Rojas

F Gonzalez-Lima

Affiliations

Soon will be listed here.

Abstract

An experimental optic neuropathy model was used to test the hypothesis that methylene blue may protect the retinal ganglion cell layer from neurodegeneration caused by rotenone. Rotenone is a widely used pesticide that inhibits complex I, the first enzyme of the mitochondrial respiratory chain. Complex I dysfunction is linked to the degeneration of retinal ganglion cells in Leber's optic neuropathy. Methylene blue is a reduction-oxidation agent that can act as a powerful antioxidant and also as an enhancer of the electron transport chain, preventing formation of mitochondrial oxygen free radicals and promoting oxygen consumption. The neurodegeneration of the retina was studied in mice with intravitreal microinjection of rotenone alone, or in combination with increasing doses of methylene blue, in one eye, and the vehicle in the contralateral control eye. The effect of rotenone and rotenone plus methylene blue was investigated using two histological stains, complex I and Nissl, and two measurements, morphometric layer thickness and non-biased stereological cell counts. Rotenone induced neurodegeneration in the retinal ganglion cell layer 24 h after injection, as indicated by significant reductions in both the thickness and cell numbers of the retinal ganglion cell layer of eyes microinjected with rotenone as compared to the control eyes. This neurodegeneration was prevented in a dose dependent manner by the injection of methylene blue along with rotenone. It was concluded that rotenone-induced degeneration in the ganglion cell layer can be prevented by intravitreal injection of methylene blue. In vitro experiments showed that methylene blue is both a powerful antioxidant as well as an enhancer of cellular oxygen consumption and is able to reverse the oxidative stress and decrease in oxygen consumption induced by rotenone in brain homogenates. The findings suggest that methylene blue may be a promising neuroprotective agent in optic neuropathy and perhaps other neurodegenerative diseases caused by mitochondrial dysfunction.

Citing Articles

Metabolic Shift and Hyperosmolarity Underlie Age-Related Macular Degeneration.

Schwartz L, Schwartz J, Henry M, Bakkar A Life (Basel). 2024; 14(9).

PMID: 39337971 PMC: 11432886. DOI: 10.3390/life14091189.

The critical role of mitochondrial lipid peroxidation in ferroptosis: insights from recent studies.

Lyamzaev K, Panteleeva A, Simonyan R, Avetisyan A, Chernyak B Biophys Rev. 2023; 15(5):875-885.

PMID: 37974984 PMC: 10643799. DOI: 10.1007/s12551-023-01126-w.

Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia.

Moren C, Treder N, Martinez-Pinteno A, Rodriguez N, Arbelo N, Madero S Antioxidants (Basel). 2022; 11(11).

PMID: 36421461 PMC: 9686909. DOI: 10.3390/antiox11112275.

Methylene blue elicits non-genotoxic HO production and protects brain mitochondria from rotenone toxicity.

Gureev A, Shaforostova E, Laver D, Khorolskaya V, Syromyatnikov M, Popov V J Appl Biomed. 2021; 17(2):107-114.

PMID: 34907732 DOI: 10.32725/jab.2019.008.

Pretreatment with Methylene Blue Protects Against Acute Seizure and Oxidative Stress in a Kainic Acid-Induced Status Epilepticus Model.

Wang Y, Luo Y, Hou G, He R, Zhang H, Yi Y Med Sci Monit. 2021; 27:e933469.

PMID: 34628461 PMC: 8513497. DOI: 10.12659/MSM.933469.

References

LINDAHL P, Oberg K . The effect of rotenone on respiration and its point of attack. Exp Cell Res. 1961; 23:228-37. DOI: 10.1016/0014-4827(61)90033-7. View

Schapira A . Human complex I defects in neurodegenerative diseases. Biochim Biophys Acta. 1998; 1364(2):261-70. DOI: 10.1016/s0005-2728(98)00032-2. View

Gonzalez-Lima F, Cada A . Cytochrome oxidase activity in the auditory system of the mouse: a qualitative and quantitative histochemical study. Neuroscience. 1994; 63(2):559-78. DOI: 10.1016/0306-4522(94)90550-9. View

Mayer B, Brunner F, Schmidt K . Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol. 1993; 45(2):367-74. DOI: 10.1016/0006-2952(93)90072-5. View

Duarte C, Ferreira I, Santos P, Carvalho A, Agostinho P, Carvalho A . Glutamate in life and death of retinal amacrine cells. Gen Pharmacol. 1998; 30(3):289-95. DOI: 10.1016/s0306-3623(97)00360-1. View

Coyle J, Puttfarcken P . Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993; 262(5134):689-95. DOI: 10.1126/science.7901908. View

Naylor G, Martin B, Hopwood S, Watson Y . A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry. 1986; 21(10):915-20. DOI: 10.1016/0006-3223(86)90265-9. View

Dreyer E, Zurakowski D, Schumer R, Podos S, Lipton S . Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996; 114(3):299-305. DOI: 10.1001/archopht.1996.01100130295012. View

Gonzalez-Lima F, Valla J . Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. Brain Res. 1997; 752(1-2):117-26. DOI: 10.1016/s0006-8993(96)01464-3. View

10.

Gunasekar P, Kanthasamy A, Borowitz J, Isom G . NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. J Neurochem. 1995; 65(5):2016-21. DOI: 10.1046/j.1471-4159.1995.65052016.x. View

11.

Nobrega J, Raymond R, Distefano L, Burnham W . Long-term changes in regional brain cytochrome oxidase activity induced by electroconvulsive treatment in rats. Brain Res. 1993; 605(1):1-8. DOI: 10.1016/0006-8993(93)91349-w. View

12.

Jung C, Higgins C, Xu Z . A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods. 2002; 114(2):165-72. DOI: 10.1016/s0165-0270(01)00524-6. View

13.

Zhang X, Jones D, Gonzalez-Lima F . Mouse model of optic neuropathy caused by mitochondrial complex I dysfunction. Neurosci Lett. 2002; 326(2):97-100. DOI: 10.1016/s0304-3940(02)00327-0. View

14.

Betarbet R, Sherer T, MacKenzie G, Panov A, Greenamyre J . Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000; 3(12):1301-6. DOI: 10.1038/81834. View

15.

Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J . NMDA-dependent superoxide production and neurotoxicity. Nature. 1993; 364(6437):535-7. DOI: 10.1038/364535a0. View

16.

Degli Esposti M . Inhibitors of NADH-ubiquinone reductase: an overview. Biochim Biophys Acta. 1998; 1364(2):222-35. DOI: 10.1016/s0005-2728(98)00029-2. View

17.

Peter C, Hongwan D, Kupfer A, Lauterburg B . Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000; 56(3):247-50. DOI: 10.1007/s002280000124. View

18.

Gonzalez-Lima F, Jones D . Quantitative mapping of cytochrome oxidase activity in the central auditory system of the gerbil: a study with calibrated activity standards and metal-intensified histochemistry. Brain Res. 1994; 660(1):34-49. DOI: 10.1016/0006-8993(94)90836-2. View

19.

Hassan H, Fridovich I . Intracellular production of superoxide radical and of hydrogen peroxide by redox active compounds. Arch Biochem Biophys. 1979; 196(2):385-95. DOI: 10.1016/0003-9861(79)90289-3. View

20.

Riha P, Bruchey A, Echevarria D, Gonzalez-Lima F . Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption. Eur J Pharmacol. 2005; 511(2-3):151-8. DOI: 10.1016/j.ejphar.2005.02.001. View