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.

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The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.

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