Vol 11, No 1 (2017)

Endogenous neurogenesis results in the formation of new neural structures that are prerequisites for numerous functions of the adult brain. Neurogenesis is promoted by a large number of regulatory processes when structural and functional support is required. Adaptive neurogenesis may be stimulated by influencing separate signaling elements, such as neuromediators and transduction, transcription, and epigenetic factors. Here, we analyze data on targeted influence on neurogenesis as a novel therapeutic approach. Neurogenesis should be considered in general as a systemic target; by influencing it, it is possible to correct functions disturbed in ischemia, stroke, neurodegenerative disorders, traumas, and psychic pathologies or to perform adaptive support and stimulation of normal physiological functions (memory, cognitive processes, social adaptation, etc.).

A proposed model of the functioning of the basal ganglia complements the existing opinions about the complex interaction between cholinergic and dopaminergic systems. A hypothesis is proposed that one of the means of interaction between these systems is the operation of a negative feedback loop. In this loop, a conditioned stimulus evokes the excitation of dopaminergic neurons and GABAergic cells with long axons in the dopaminergic nuclei, which leads to an increase in the influence on dopamine D2 receptors on striatal cholinergic interneurons; an increase in their inhibition can lead to a pause in their responses. In turn, during this pause reduced action on presynaptic nicotinic receptors at axon terminals of dopaminergic neurons results in a decrease in dopamine release. In addition, dopaminergic neurons are under the inhibitory action of GABAergic striatonigral cells in the striosomes of the dorsal striatum and clusters in the ventral striatum. During the pause, stimulation of M2/M4 receptors located on these striatonigral cells weakens, which should promote potentiation of their excitation, subsequent enhancement of the inhibition of dopaminergic cells, and a decrease in the dopamine concentration in the striatum. In addition, a decrease in the stimulation of M1 receptors on striatopallidal cells and M2 receptors on striatonigral cells of the matrix during the pause should promote synergistic disinhibition through the direct and indirect pathways via the basal ganglia of certain groups of thalamic neurons and enhancement of the excitation of neocortical neurons connected with them. This interaction between cholinergic and dopaminergic systems contributes to the normal functioning of the various parallel cortico–basal ganglia–thalamocortical loops, which play a determining role in movement choice, sensory perception, learning, and intentional behavior. The proposed model implies that cholinergic and dopaminergic denervation of different structures, as well as changes in the density and affinity of receptors that are sensitive to acetylcholine, dopamine, and NMDA, which are typical for Alzheimer’s and Parkinson’s diseases, should lead to abnormal functioning of these loops. This may underlie various cognitive and motor disorders.

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. The standard postoperative chemotherapy is temozolomide (TMZ), which does not greatly improve survival. The DNA repair gene O-6-methylguanine-DNA methyltransferase (MGMT) contributes to the response of TMZ-induced DNA damage. The commonly prescribed antiepileptic drug levetiracetam (LEV) has been shown to enhance TMZ’s antitumor effect via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of the LEV and TMZ combination remain poorly understood. Mechanisms of response to chemotherapy include apoptosis and mitotic catastrophe, and recent studies have suggested that premature senescence may also be invoked when cancer cells are exposed to therapeutic agents. In our study, we evaluated cell proliferation and premature senescence after single and combined treatments of TMZ and LEV in two GBM cell lines that differ in TMZ sensitivity caused by the absence (A172) or presence (T98) of the MGMT protein. Both LEV and TMZ reduced cell proliferation in a dose-dependent manner in A172 cells. A senescent-like phenotype, as determined by β-galactosidase activity, was induced by both TMZ and LEV. Overall, there was a greater effect following combined treatment compared to the monotherapy groups. Thus, LEV appears to have a tumor-suppressive effect and induces cellular senescence, and combined treatment of LEV and TMZ enhanced these effects. because LEV treatment results in few adverse effects, its use in GBM treatment may allow for reduction of the TMZ dose to enhance the clinical efficacy of TMZ chemotherapy and improve quality of life.

The effects of testosterone and progesterone on the activities of carboxypeptidase E and phenylmethylsulfonyl fluoride-inhibited carboxypeptidase (PMSF-CP) after stress induced by an intraperitoneal injection of olive oil were studied in male and female mice. Sex-related differences in the activities of the studied carboxypeptidases were observed in both intact and stress-exposed animals, as well as after the injection of the steroid hormones. In females, stress and hormones mostly decreased the activity of carboxypeptidases, which resulted in the attenuation of differences between females and males. The alterations in the PMSF-CP activity were stronger than in the activity of carboxypeptidase E. The involvement of these enzymes in the mechanism of stress and formation of sex-related differences in the functioning of the hypothalamo–pituitary–adrenal system, as well as the mechanism of the effects of sex-steroid hormones on the activities of these carboxypeptidases, are discussed.

It was shown that serpinb1a is expressed during differentiation of PC12 cells induced by nerve growth factor (NGF). Here, we found that overexpression of serpinb1a in PC12 cells weakly but significantly increases PC12 survival during staurosporine-induced apoptosis. Immunoprecipitation of serpinb1a after its overexpression in PC12 showed that this protein interacts with active caspase-3 in both resting cells and cells that were stimulated by staurosporine. NGF-induced PC12 differentiation resulted in the formation of outgrowths and a considerable increase in caspase-3 activity in 24 h after the beginning of NGF treatment. This increase in the activity of caspase-3 lasted for at least 48 h. Overexpression of serpinb1a in PC12 cells suppressed the growth of neurites during NGF-induced differentiation; this effect was observed only at 48 h. Experiments performed with primary cultures of neocortical and hippocampal neurons showed that serpinb1a overexpression results in relatively weak changes in morphology: serpinb1a decreased the number of secondary dendrites in the cortical and average length of secondary dendrites in hippocampal neurons. The results of the experiments suggests that serpinb1a may interact with caspase-3 and influence the differentiation of PC12 cells but not neuronal cells.

Activation of extrasynaptic NMDA receptors by high glutamate concentrations is one of the key pathogenic factors following a stroke. For this reason, the search for efficient neuroprotective agents that could reduce glutamate toxicity is a pressing need. Ca²⁺ overload in response to glutamate leads to activation of signaling cascades in the cell and the development of oxidative stress, which ultimately leads to apoptosis. Using a model system of acute excitotoxicity caused by 50 μM NMDA, which was used as a specific NMDA receptor activator, we demonstrated that during 2 hours of incubation the viability of the primary neuronal culture decreased by 30–50%. To demonstrate that the observed effect is associated not only with the Ca²⁺ influx into the cytoplasm through the activated NMDA receptors, we decreased the Ca²⁺ concentration in the medium. The lowered Ca2+ concentration, as well as its complete absence, did not affect NMDA toxicity. We tested carnosine, a naturally occurring dipeptide and promising antioxidant, as a neuroprotective agent. The addition of 2 mM carnosine prevented the decrease in cell viability caused by a 2-hour incubation with 50 μM NMDA, while it showed no effect on the viability of the cell culture in the control. Based on the results, we consider the further study of carnosine, its complexes, and analogues as neuroprotectors in cerebral ischemia promising.

The functioning of the heart is under the tight control of the sympathetic division of the autonomous nervous system. The terminals of the postganglionary fibers release both noradrenaline (NA), which is the major sympathetic neurotransmitter, and comediators that can contribute to the fine “tuning” of the adrenergic control of cardiac function. Purine compounds, such as diadenosine pentaphosphate (Ар5А), as well as nicotinamide adenine dinucleotide (NAD+), can act as comediators. The distinctive features of the effects of these compounds on the heart have been incompletely characterized. It is not clear whether these compounds can act as comediators, i.e., to modulate the sympathetic (adrenergic) activity in the heart. Exogenous extracellular Ар5А was shown to reduce the contractility of the ventricular myocardium and to suppress conduction in the atrioventricular (AV) junction in a Langendorff-perfused isolated rat heart. Extracellular NAD⁺ had a weak effect on inotropy but induced a negative dromotropic effect in the AV junction, similarly to Ар5А. We found that Ар5А and NAD⁺ suppress both the positive inotropic effect of noradrenaline in the ventricular myocardium and the positive dromotropic effect of NA in the AV junction. The “inhibitory” effects of both purine compounds were more pronounced in the case of combined application with NA. In addition, the influence of Ар5А and NAD⁺ on the effects of noradrenaline was shown to depend on the timing of the application of these compounds. Our results suggest that the role of the sympathetic comediators NAD⁺ and Ар5А may consist of the limitation of noradrenaline effects and/or the effects of sympathetic stimulation in the heart.

Lithium is used in the therapy of various psychoses based on its antidepressant and mood stabilizing properties. However it also exerted toxic side effects in long standing treatment. We studied the effect of lithium on brain oxidative stress status into healthy rat as well as the putative protection afforded by grape seed and skin extract, used as an antioxidant and anti-inflammatory agent. Lithium generated an oxidative stress characterized by increased lipoperoxidation and carbonylation, decreased antioxidant enzyme activities as catalase, superoxide dismutase and glutathione peroxidase. Furthermore lithium altered transition metals distribution and associated enzyme activities, increased intracellular mediators as H₂O₂, free iron, calcium, magnesium and calpain activity but decreased acetylcholinesterase activity. Lithium also disturbed brain lipidemia as evidenced by high triglyceride and cholesterol and low lipase activity. Almost all deleterious effects of lithium were normalized by grape seed and skin extract especially at the therapeutic doses of lithium. Grape seed and skin extract could be proposed as an efficient neuroprotectant to mitigate the adverse side effects of lithium.

Cortexin, a drug that contains a hydrolysate of brain peptides, has long been used in clinics; however, the mechanisms of its action remain obscure. We attempted to identify the brain proteins that interact with peptides of Cortexin using affinity chromatography. The spectrum of proteins that bound with Cortexin peptides was different in liver and brain homogenates. Four brain proteins that interact with peptides of Cortexin have been identified: three brain-specific proteins, viz., tubulin β5, creatine kinase B-type, and 14-3-3 α/β, as well as the cytoskeletal protein actin, which is abundant in many tissues. These proteins may be molecular targets for Cortexin peptides and be responsible for the neuroprotective effects of the drug.

The objective of this study is to investigate the relationship between anthropometric (BMI and waist circumference), metabolic (glucose, insulin, insulin resistance, HbA1c, and lipid profile), psychopathologic (Positive and Negative Syndrome Scale, PANSS) parameters with vitamin D and serum brainderived neurotrophic factor (BDNF) levels in patients with schizophrenia. The study population consisted of 54 healthy control subjects, and 64 volunteer patients, monitored in the psychiatry outpatient clinics of Antalya Education and Research Hospital. Serum glucose, HDL, LDL, triglyceride, total cholesterol levels (spectrophotometric method), HbA1c (HPLC method), insulin, and vitamin 25(OH)D (chemiluminescence method), with HOMA-IR (numerical calculation), and serum BDNF levels (sandwich ELISA, enzymelinked immunosorbent assay) were quantitatively evaluated using respective analytical methods indicated in parentheses. Twenty-seven (42.18%) of 64 schizophrenia patients were diagnosed with MetS. In schizophrenia patients diagnosed with metabolic syndrome (MetS), PANSS-negative and -positive symptom scores were significantly higher, while serum BDNF levels were significantly lower. In patients with schizophrenia, significantly negative correlations were detected between PANSS-negative and -positive symptom scores, and BDNF (p < 0.001 and p < 0.001, respectively), and also between PANSS-negative symptom score and vitamin D (p = 0.022). Lower serum BDNF levels may be related to increases in the possible development of MetS and psychotic symptoms. Decrease in vitamin D levels in schizophrenia patients may be associated with an increase in PANSS-negative symptom scores. In schizophrenia patients with MetS, psychotic symptoms may be more severe.