Beneficial network effects of methylene blue in an amnestic model

Abstract

Posterior cingulate/retrosplenial cortex (PCC) hypometabolism is a common feature in amnestic mild cognitive impairment and Alzheimer's disease. In rats, PCC hypometabolism induced by mitochondrial dysfunction induces oxidative damage, neurodegeneration and memory deficits. USP methylene blue (MB) is a diaminophenothiazine drug with antioxidant and metabolicenhancing properties. In rats, MB facilitates memory and prevents neurodegeneration induced by mitochondrial dysfunction. This study tested the memory-enhancing properties of systemic MB in rats that received an infusion of sodium azide, a cytochrome oxidase inhibitor, directly into the PCC. Lesion volumes were estimated with unbiased stereology. MB's network-level mechanism of action was analyzed using graph theory and structural equation modeling based on cytochrome oxidase histochemistry-derived metabolic mapping data. Sodium azide infusions induced PCC hypometabolism and impaired visuospatial memory in a holeboard food-search task. Isolated PCC cytochrome oxidase inhibition disrupted the cingulo-thalamo-hippocampal effective connectivity, decreased the PCC functional networks and created functional redundancy within the thalamus. An intraperitoneal dose of 4 mg/kg MB prevented the memory impairment, reduced the PCC metabolic lesion volume and partially restored the cingulo-thalamo-hippocampal network effects. The effects of MB were dependent upon the local sub-network necessary for memory retrieval. The data support that MB's metabolic-enhancing effects are contingent upon the neural context, and that MB is able to boost coherent and orchestrated adaptations in response to physical alterations to the network involved in visuospatial memory. These results implicate MB as a candidate intervention to improve memory. Because of its neuroprotective properties, MB may have disease-modifying effects in amnestic conditions associated with hypometabolism.

H2S induced coma and cardiogenic shock in the rat: Effects of phenothiazinium chromophores

“…15 This effect has been put forward to explain the beneficial effects of MB during sodium azide 21 or cyanide 24 poisoning. Both these agents share the same inhibitory effect on mitochondrial function as H 2 S. Finally, MB may have antagonized the blocking effects of H 2 S on calcium channels.…”

“…18 These effects clearly antagonize the mechanism of hydrogen sulfide toxicity on mitochondrial function. 6,7,19,20 In keeping with this property, MB has been shown to exert a remarkable protection against the toxic effects of sodium azide, 21 which is, like H 2 S, a poison of the mitochondrial activity. This effect has been observed when MB was injected only once after sodium azide exposure, 21 or for a few days during chronic sodium azide intoxication.…”

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

“…Hypometabolism in the posterior cingulate/retrosplenial cortex is a common feature in amnestic mild cognitive impairment and AD [17], [18]. In rats with metabolic lesions, MB treatment reduced metabolic lesion volume in the posterior cingulate/retrosplenial cortex, restored the function of the cingulo-thalamo-hippocampal network, and improved memory [19]. MB also enhances mitochondrial complex IV (cytochrome c oxidase) activity and therefore has been proposed as a metabolic enhancer that attenuates neurodegeneration induced by metabolic challenge [20], [21].…”

Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain

“…Methylene blue also prevented chronic spatial memory impairment in a rat model of Alzheimer disease on the basis of cytochrome c oxidase inhibition, implicating causality between mitochondrial respiration and memory enhancement by methylene blue (12). Methylene blue also prevented memory impairment in rats with local inhibition of mitochondrial respiration in the posterior cingulate cortex by maintaining cingulo-thalamo-hippocampal effective connectivity (13). Besides improving mitochondrial respiration, methylene blue could have pleiotropic effects on the brain from its redox interactions with various proteins and cellular processes (14,15).…”