Neuronal excitotoxicity which is induced by exposure to excessive extracellular glutamate is shown to be involved in neuronal cell death in acute brain injury and a number of neurological diseases. High concentration of glutamate induces calcium deregulation which results in mitochondrial calcium overload and mitochondrial depolarization that triggers the mechanism of cell death. Inhibition of mitochondrial calcium uptake could be potentially neuroprotective but complete inhibition of mitochondrial calcium uniporter could result in the loss of some physiological processes linked to Ca²⁺ in mitochondria. Here, we found that a novel compound, TG-2112x, can inhibit only the lower concentrations mitochondrial calcium uptake (induced by 100 nM-5 μM) but not the uptake induced by higher concentrations of calcium (10 μM and higher). This effect was not associated with changes in mitochondrial membrane potential and cellular respiration. However, a pre-treatment of neurons with TG-2112x protected the neurons against calcium overload upon application of toxic concentrations of glutamate. Thus, sequestration of mitochondrial calcium uptake protected the neurons against glutamate-induced mitochondrial depolarization and cell death. In our hands, TG-2112x was also protective against ionomycin-induced cell death. Hence, low rate mitochondrial calcium uptake plays an underestimated role in mitochondrial function, and its inhibition could protect neurons against calcium overload and cell death in glutamate excitotoxicity.

This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer’s disease. The pathogenesis of Alzheimer’s disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk factor for both pathologies is aging. Common pathological mechanisms include both factors in the development of oxidative stress, neuroinflammation, insulin resistance, and amyloidosis, as well as impaired mitochondrial dysfunctions and increasing cell death. The currently available drugs for the treatment of type 2 diabetes and Alzheimer’s disease have limited therapeutic efficacy. It is important to note that drugs used to treat Alzheimer’s disease, in particular acetylcholinesterase inhibitors, show a positive therapeutic potential in the treatment of type 2 diabetes, while drugs used in the treatment of type 2 diabetes can also prevent a number of pathologies characteristic for Alzheimer’s disease. A promising direction in the search for a strategy for the treatment of type 2 diabetes and Alzheimer’s disease may be the creation of complex multi-target drugs that have neuroprotective potential and affect specific common targets for type 2 diabetes and Alzheimer’s disease.

The currently available experimental data supports the hypothesis that the neuroprotective effect of dimebon is related to the protection of the brain-mitochondria from neurodegeneration. In this study, the influence of dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effects of this drug. Here, we demonstrate that dimebon enhances the resistance of the isolated rat brain and liver mitochondria to the induction of mitochondrial permeability transition (MPT) by calcium ions even in the presence of atractyloside, a MPT pore (MPTP) opener, but is ineffective against atractyloside-induced mitochondria swelling. Unlike cyclosporine A (CsA), a MPTP inhibitor, Dimebon does not influence the adenine nucleotide translocase (ANT) conformational changes and is not able to prevent the MPT of de-energized mitochondria. Using three different assays, and using amyloid-β peptide for inducing mitochondrial toxicity, we show that the influence of dimebon on the calcium retention capacity (CRC) of mitochondria depends on the mode of calcium addition. No obvious influence of dimebon on CRC was observed under the conditions of calcium infusion in the pump mode but the increase of CRC of rat brain mitochondria was observed when calcium was added in the bolus mode; the addition of calcium in the single pulse mode led to the increase of the lag period of calcium efflux from mitochondria. From these studies it is shown that dimebon is effective against amyloid-β (Aβ) potentiated mitochondrial swelling and decrease of calcium retention capacity (CRC) of the brain mitochondria.

Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder.

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.