Human aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer’s disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).

The disruption of homeostasis of zinc (Zn²⁺) and copper (Cu²⁺) ions in the central nervous system is involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Wilson’s, Creutzfeldt-Jakob, Parkinson’s, and Alzheimer’s diseases (AD), and traumatic brain injury (TBI). The last two pathological conditions of the brain are the most common; moreover, it is possible that TBI is a risk factor for the development of AD. Disruptions of Zn²⁺ and Cu²⁺ homeostasis play an important role in the mechanisms of pathogenesis of both TBI and AD. This review attempts to summarize and systematize the currently available research data on this issue. The neurocytotoxicity of Cu²⁺ and Zn²⁺, the synergism of the toxic effect of calcium and Zn²⁺ ions on the mitochondria of neurons, and the interaction of Zn²⁺ and Cu²⁺ with β-amyloid (Abeta) and tau protein are considered.

Oxidative stress is one of the main pathogenic factors of neuron damage in neurodegenerative processes; this makes it an important therapeutic target to which the action of neuroprotectors should be directed. One of these drugs is thymoquinone. According to modern data, this substance has a wide range of pharmacological activity, including neuroprotective, which was demonstrated in experimental modeling of various neurodegenerative diseases and pathological conditions of the brain. The neuroprotective effect of thymoquinone is largely due to its antioxidant ability. Currently available data show that thymoquinone is an effective means to reduce the negative consequences of acute and chronic forms of cerebral pathology, leading to the normalization of the content of antioxidant enzymes and preventing an increase in the level of lipid peroxidation products. Antioxidant properties make this substance a promising basis for the development of prototypes of therapeutic agents aimed at the treatment of a number of degenerative diseases of the central nervous system.

Thymoquinone is one of the main active components of the essential oil from black cumin (Nigella sativa) seeds. Thymoquinone exhibits a wide range of pharmacological activities, including neuroprotective action demonstrated in the models of brain ischemia/reperfusion, Alzheimer’s and Parkinson’s diseases, and traumatic brain injury. The neuroprotective effect of thymoquinone is mediated via inhibition of lipid peroxidation, downregulation of proinflammatory cytokines, maintenance of mitochondrial membrane potential, and prevention of apoptosis through inhibition of caspases-3, -8, and -9. Thymoquinone-based mitochondria-targeted antioxidants are accumulated in the mitochondria and exhibit neuroprotec-tive properties in nanomolar concentrations. Thymoquinone reduces the negative effects of acute and chronic forms of brain pathologies. The mechanisms of the pharmacological action of thymoquinone and its chemical derivatives require more comprehensive studying. In this paper, we formulated the prospects of application of thymoquinone and thymoquinone-based drugs in the therapy of neurodegenerative diseases.

This study assesses a protective effect of a mitochondria-targeted antioxidant SkQT1 (a mixture of 10-(6'-toluquinonyl) decyltriphenylphosphonium and 10-(5'-toluquinonyl) decyltriphenylphosphonium in proportion of 1.4:1), using an open focal trauma model of the rat brain sensorimotor cortex and a model of amyloid-beta1-42 (Abeta)-induced impairment of hippocampal long-term potentiation (LTP), a kind of synaptic plasticity associated with learning and memory. It was found that a trauma-induced neurological deficit could be partially improved with daily intraperitoneal injections of SkQT1 (250 nmol/kg) for 5 days after the trauma. Neither an analog of SkQT1 without thymoquinone (C12TPP) nor original thymoquinone without a cation residue was effective to improve such conditions. In the SkQ molecule, the phosphonium cation can be replaced by the rhodamine 19 cation, with the SkQTR1 being still active in the treatment of the neurological deficit. Application of 200 nM Abeta to rat hippocampal slices impaired the induction of LTP in the hippocampal CA1 pyramidal layer. A single intraperitoneal injection of SkQT1 (250 nmol/kg body weight) made 24 h before the slice preparation prevented the harmful effect of Abeta on the LTP. Thus mitochondria-targeted antioxidants, containing thymoquinone, have neuroprotective properties.

Neuronal plastic rearrangements during the development and functioning of neurons are largely regulated by trophic factors, including nerve growth factor (NGF). NGF is also involved in the pathogenesis of Alzheimer’s disease. In the brain, NGF is produced in structures innervated by basal forebrain cholinergic neurons and retrogradely transported along the axons to the bodies of cholinergic neurons. NGF is essential for normal development and functioning of the basal forebrain; it affects formation of the dendritic tree and modulates the activities of choline acetyltransferase and acetylcholinesterase in basal forebrain neurons. The trophic effect of NGF is mediated through its interactions with TrkA and p75 receptors. Experimental and clinical studies have shown that brain levels of NGF are altered in various pathologies. However, the therapeutic use of NGF is limited by its poor ability to penetrate the blood–brain barrier, adverse side effects that are due to the pleiotropic action of this factor, and the possibility of immune response to NGF. For this reason, the development of gene therapy methods for treating NGF deficit-associated pathologies is of particular interest. Another approach is creation of low molecular weight NGF mimetics that would interact with the corresponding receptors and display high biological activity but be free of the unfavorable effects of NGF.