Vol 11, No 2 (2017)

The principal mechanism of the pathogenesis of Parkinson’s disease is accumulation and aggregation of alpha-synuclein. While the normal function of alpha-synuclein is the control of vesicular neurotransmission, its pathogenic effects influence different cell functions, including the activities of mitochondria and proteasomes, as well as autophagic protein degradation. It is noteworthy that the same functions are affected when the renewal of macromolecules and organelles is impaired as a result of normal aging. Since aging is the principal risk factor for Parkinson’s disease, it is very important to analyze its molecular and cellular consequences in the context of alpha-synuclein pathology. Here, we review the similarities and differences between normal brain aging and Parkinson’s disease, with a focus on nigral dopaminergic neurons, which seem to be specifically sensitive to the combined damage induced by alpha-synuclein and aging. Elucidating the mechanism that underlies the death of dopaminergic neurons in Parkinson’s disease is essential not only for the understanding of its general pathogenesis but also for the development of approaches to its early preclinical diagnosis and preventive therapy.

Based on the known experimental data on the specific morphological and neurochemical changes in the neural circuits involved in the occurrence of paradoxical sleep (REM sleep) that are observed in Alzheimer’s disease (AD) and our analysis of the effects of neuromodulators on the functioning of these circuits we propose that REM sleep deficiency in AD is caused by the following mechanisms: (1) the activity of the lateral geniculate body and occipital cortex is not sufficient to generate the ponto-geniculo-occipital (PGO) waves that are specific for REM sleep due to lower activity of cholinergic cells of the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDTN) and lower density of cholinergic receptors; (2) because of reduced activity of cholinergic neurons of the PPN and LDN on GABAergic interneurons projecting to noradrenergic and serotonergic cells, the activity of the latter cannot be completely inhibited, as should occur during REM sleep; (3) the concentration of melanin-concentrating hormone is not sufficient for sleep due to the decreased activity of cholinergic cells of the basal forebrain nucleus, which excite neurons that produce this hormone; and (4) the activity of histaminergic cells increases and the activity of neurons that release melanin-concentrating hormone decreases due to the increased orexin level. Our analysis shows that common use of drugs that increase the acetylcholine concentration in patients with AD may result in increased activity of orexinergic cells and this must prevent the occurrence of REM sleep. We hypothesize that microstimulation of PPN may improve the occurrence of REM sleep because it should decrease the activity of serotoninergic, noradrenergic, and histaminergic cells and promote the generation of PGO waves and hippocampal theta activity. This treatment may improve the conditions for memory consolidation in patients with AD. Such microstimulation should be applied at night according to a special protocol.

The dynamics of the expression of the HIF factor-1 α-subunit, which is related to products of early genes, has been studied in the neocortex, the hippocampus, and the hypothalamus of rats during the development of posttraumatic stress disorder (PTSD) in a stress–restress model and using triple moderate hypobaric hypoxia (MH₃), which prevents the formation of this anxiety pathology. The immunohistochemical method has shown that after pathogenic traumatic stress (TS), during the primary (“hidden”) period of modeled PTSD formation, the level of HIF-1α expression did not change significantly; however, after restress it rapidly increased in all regions of the brain. An increased expression of this factor remained in animals with experimental PTSD for up to 10 days after restress. Exposure to MH₃ before TS or before restress compensated for these disturbances: fully in the hippocampus and partly in the neocortex; it inhibited the prolonged over-induction of the HIF-1α, which may be one of the mechanisms that mediate an anxiolytic effect of hypoxia. Along with this, preconditioning with MH₃ significantly decreased the content of HIF-1α after TS, thus preventing activation of the HIF-1 factor during the hidden period, which is likely associated with the formation of pathological reactivity to restress. These facts indicate the pathogenetic role of HIF-1 in certain periods of experimental PTSD and the correcting effect of hypoxic preconditioning.

The dynamics of the expression of the neuronal NO-synthase and microglia activity in the spinal centers of pain modulation were studied on the ligated rat sciatic nerve. The development of neuropathic pain causes an increase in the activity of neuronal NO-synthase and the iba-1-positive microglia in the spinal ganglia and the surface laminae of the posterior horn of the spinal cord, which dynamically corresponds to the severity of pain. At the same time, the dynamics of NO-ergic activity are parallel with the activation of microglia in these brain structures. Thus, we cannot exclude the direct inter-modulating effects of spinal microglia and NO-ergic nociceptive neurons.

Peripheral tissue damage or nerve injury often leads to development of pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia that persist for years or decades after all possible tissue healing has occurred. The modification of classic formalin test with two subsequent injections of formalin can be useful to investigate central mechanisms of “pain memory”. To evaluate the effect of analgesia of periphery on central pathways of nociception we used four groups of analgesics: a local anaesthetic-lidocaine, NSAID-diclofenac, a mu-opioid receptor agonist-DAMGO, anticonvulsant with chronic pain-relieving action-gabapentin. We studied the impact of analgesic drugs on acute and chronic pain conditions taking as a basis c-Fos as a pain intensity marker.

We present a comprehensive clinical and biological study of 46 patients with depressive disorder (F32-F33: depressive episode and recurrent depressive disorder) during pharmacotherapy. Neurohumoral factors (cortisol, brain-derived neurotrophic factor, serotonin, DHEA and its sulfated form) were determined in serum by ELISA. The severity of the current depressive episode was evaluated using the 17-point Hamilton Depression Rating Scale (HDRS-17); the pharmacotherapy efficacy was evaluated using the scale of the Clinical Global Impression (CGI Scale). We showed that before prescription of pharmacotherapy peripheral blood neurohumoral markers that characterize the state of stress-realizing and stress-limiting systems of the body may be considered as biological predictors of the effective pharmacotherapy of a current depressive episode and used as additional paraclinical examination methods. At higher concentrations of cortisol and serotonin associated with a decrease in the content of neurosteroid dehydroepiandrosterone, the high efficiency of the pharmacotherapy of depressive episode is predicted.