Cellular and molecular actions of Methylene Blue in the nervous system

Abstract

Methylene Blue (MB), following its introduction to biology in the 19 th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the first line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide-induced encephalopathy, and is routinely employed as a diagnostic tool in surgical procedures. Furthermore, recent studies suggest that MB has beneficial effects in Alzheimer's disease and memory improvement. Although the modulation of the cGMP pathway is considered the most significant effect of MB, mediating its pharmacological actions, recent studies indicate that it has multiple cellular and molecular targets. In the majority of cases, biological effects and clinical applications of MB are dictated by its unique physicochemical properties including its planar structure, redox chemistry, ionic charges, and light spectrum characteristics. In this review article, these physicochemical features and the actions of MB on multiple cellular and molecular targets are discussed with regard to their relevance to the nervous system.

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

“…visual cycle activity, we postulate that either modest inhibition of visual cycle activity that has no discernible effect on normal vision or normalization of superoxide release from mitochondria in diabetes could decrease oxidative stress and the subsequent development of retinopathy. Methylene blue potently inhibits superoxide generation by the retina in diabetes, although it has multiple other reported effects as well (41).…”

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

“…In addition, we find that MB treatment improves HGPS heterochromatin organization and corrects the expression of more than 50% of the misregulated genes in the HGPS nucleus (Figs 5E–G and 6). As a highly permeable molecule, it is known that MB can potentially enter all the other cellular compartments, including the nucleus (Kelner et al ., 1988; Atamna & Kumar, 2010; Oz et al ., 2011). Thus, the results in the nucleus were encouraging but not completely unexpected.…”

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

“…Electrophoresed proteins were transferred to polyvinylidene difluoride membranes (Bio-Rad) that were blocked in blocking buffer (1% (w/v) nonfat dry milk in TBS containing 0.1% (v/v) Tween 20) for 1 h at ambient temperature. Membranes were then hybridized for 1 h at ambient temperature with primary antibodies as follows: a carboxyl-terminal APP polyclonal antibody (1:400, IBL); a carboxyl-terminal PS1 monoclonal antibody (PS1-loop; 1:500, Merck Millipore); a carboxyl-terminal BACE1 polyclonal antibody (1:400, IBL); a carboxyl-terminal BACE monoclonal antibody (61-3E7, 1:1,000, Merck Millipore); an amino-terminal A␤ 1-16 monoclonal antibody (82E1; 1:150, IBL), an amino-terminal A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] monoclonal antibody (6E10; 1:1,000, Merck Millipore); a nicastrin polyclonal antibody (corresponds to amino acid residues 688 -708 from human nicastrin) (1:1000, Thermo Fisher Scientific, Waltham, MA); an amino-terminal presenilin enhancer 2 (PEN-2) polyclonal antibody (1:250, Thermo Fisher Scientific); an actin polyclonal antibody (1:500, Santa Cruz Biotechnology, Santa Cruz, CA) as a loading control, or a ␤-actin monoclonal antibody (AC-74, 1:4,000, Sigma) as a loading control. Membranes were then rinsed three times for 30 min each in TBS containing 0.1% (v/v) Tween 20 and incubated for 1 h at ambient temperature with appropriate horseradish peroxidase-conjugated secondary antibodies.…”

“…Current indications for MB include treatment for enzymopenic hereditary methemoglobinemia and acute acquired methemoglobinemia, ifosfamide-induced encephalopathy, urinary tract infections in elderly patients, vasoplegic adrenaline-resistant shock, and pediatric malaria. Additionally, MB is routinely employed as a diagnostic tracer dye in surgical procedures (8,9). In the context of neurological diseases, the beneficial effects of MB have been demonstrated for treatment of psychosis in both preclinical (10,11) and clinical studies (12)(13)(14).…”

“…In the context of neurological diseases, the beneficial effects of MB have been demonstrated for treatment of psychosis in both preclinical (10,11) and clinical studies (12)(13)(14). Moreover, MB may also have beneficial effects on cognitive performance in AD patients (8). In this regard, promising results from a phase II clinical trial of MB (methylthioninium chloride, Rember TM ) for mild-to-moderate AD patients showed significantly improved cognitive function after 6 months of treatment compared with placebo control, and this led to stabilized AD progression over the course of a year (15,16).…”