Vol 13, No 2 (2019)

We review the role of disorders of one-carbon metabolism (OCM) in the etiopathogenesis of schizophrenia, define directions for further research into the role of single nucleotide genetic polymorphisms of the folate pathway enzymes, and outlined future lines of studies on personalized correction of OCM disorders. The reviewed data suggest that it is necessary to perform complex studies on the genetic risk of OCM disorders, molecular mechanisms of schizophrenia pathogenesis, which involve OCM disorders, and the clinical effects of their personalized correction.

Disturbances of learning and memory are related to the impaired expression of rhythmic activity and phase synchronization in the hippocampus, entorhinal cortex, and other cortical areas. Several structures involved in the generation of the theta rhythm contain cholinergic cells and thus, acetylcholine concentration has to affect the parameters of the rhythm and play a substantial role in learning and memory. Here, we analyzed possible mechanisms of the effect of acetylcholine on the parameters of the theta rhythm in the hippocampus. The complex nature of these mechanisms is related to the effects of the cholinergic input from the medial septum to the hippocampus and the input from cholinergic cells of the pedunculopontine and oral pontine nuclei as well as of the Meynert nucleus on theta activity. Furthermore, the thalamic nucleus reu-niens, which also sends projections to the medial septum, hippocampal CA1 field, and entorhinal cortex, also affects theta activity. The supramamillary, posterior and medial mamillary nuclei of the hypothalamus also influence it via their interaction with the hippocampal formation and septum. Some structures involved in the generation of theta activity have long axon GABAergic cells, which exhibit inhibitory or disinhibitory effects on other structures. Acetylcholine, which contributes to increased excitation in the network involved in the generation of the theta rhythm, can lead to an increase in its expression or power, while the rhythm frequency is determined by inhibition and should increase when the inhibition is weakened.

Despite numerous studies, there is still no clear idea on the fine mechanisms of dysfunction of the brain dopamine system during the formation of alcohol dependence. In this work, we studied the expression of genes that encode tyrosine hydroxylase (TH), a key enzyme of dopamine synthesis, dopamine transporter (DAT), dopamine receptors of the second subtype (DRD2) in the midbrain, and dopamine receptors of the first and second subtypes (DRD1 and DRD2) in the striatum of rats that consumed alcohol from the 60th to 120th days of life in the “free choice” paradigm. The most pronounced changes, a decrease in mRNA expression of DRD1 and DRD2 in the striatum, as well as DAT and TH in the midbrain, were observed in animals with a growing preference for alcohol compared to a group of rats that controlled consumption at a constantly low level. In animals with initially stable high levels of alcohol preference, a decrease in the relative expression level of DRD1 and DRD2 mRNA in the striatum was found, while there was no difference in the expression of DAT and TH mRNA in the midbrain. The expression level of DRD2 mRNA in the midbrain did not differ in all the studied groups. These data suggest that changes in the expression of mRNA of DRD1 and DRD2 in the striatum do not depend on the initial alcohol preference and are determined by the level of alcohol intoxication, while the decrease in the level of TH and DAT mRNA in the midbrain may be one of the mech-anisms of loss of control over consumption.

Melatonin (MEL) is a hormone produced by the pineal gland. It easily penetrates the cell membrane and may be accumulated in the mitochondria at high concentrations and improve their functional state. However, there are also data that show that the effect of MEL on mitochondria may greatly vary, i.e., it depends on the type of tissue, the conditions of administration, and the composition and structural features of the target molecules. In the present work, we studied the effect of MEL on the functional state of rat brain mitochondria when it is directly added to mitochondria under conditions of opening of the nonspecific mito-chondrial permeability transition pore (mPTP), as well as the effects on the levels of mPTP regulators (VDAC and CNPase) and the main subunits of the electron transport chain (ETC). It was found that the direct addition of MEL at a concentration of 10 nM and 100 nM to mitochondria leads to a change in the protein level of the first and fourth ETC complexes, initiation of mPTP opening, as well as a decrease in the levels of proteins that regulate mPTP function. These data suggest that MEL may act as a pro-apoptotic agent, which may have important biological and pharmacological significance.

Single administration of methotrexate at a dose of 0.1 mg/kg on the first and seventh days is associated with an imbalance in the pool of low-molecular weight sulfur-containing compounds whose severity decreases in the following series: hypothalamus > midbrain > cerebral hemispheres > striatum > cerebellum. In 24 h, homocysteine remethylation in the cerebral hemispheres decreases, transsulfuration activity in the striatum increases, taurine synthesis in the midbrain decreases, homocysteic acid and taurine synthesis in the hypothalamus increases, and, in the cerebellum, the oxidase pathway of cysteine and homocysteine transformation are activated and taurine transsulfuration and biosynthesis is inhibited. At 7 days after a single meth-otrexate administration, the general trend included the inhibition of the oxidation reactions and activation of transsulfuration and decarboxylation in taurine synthesis.

Temporal lobe epilepsy (TLE) is the most prevalent subtype of epilepsy in humans and can easily develop into refractory epilepsy. The development of TLE is a complex process involving acute insults, a latent period, and chronic recurrent seizures. The latent period could provide an opportunity for intervention if molecular targets were to be identified. Collapsin response mediator protein 2 (CRMP2) was recently found to be involved in the mechanism of epileptogenesis. However, the results were inconsistent. We aimed to determine if CRMP2 is differentially expressed in rats following status epilepticus (SE), and to validate the expression of CRMP2 during the latent period. We used kainic acid (KA) as the initial insult to induce SE in rats and applied two-dimensional gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MALDI-TOF/TOF) to search for aberrant protein expression in the hippocampus. Western blots were used to confirm the expression level of proteins. Protein extracts of the hippocampus from the sham and the KA groups were separated by 2D-DIGE; 17 protein spots on the gel, representing 10 unique proteins, were found to be significantly different between the KA and sham groups. Among those, CRMP2 was significantly up-regulated. Results of western blot analysis confirmed the increased CRMP2 levels in the KA group. Our findings indicate that the increase in CRMP2 during the latent period is possibly involved in the mechanism of epileptogenesis and is expected to be a novel therapeutic target.

The prenatal stress during pregnancy has a wide variety of negative effects on the offspring behaviors. As such, in the present study the effect of prenatal immobilization stress was investigated on the brain BDNF level, spatial memory, anxiety and depression-like behavior in the F1 generation female NMRI mice. Twenty female pregnant mice were randomly allocated to stress and control groups (n = 10/group). The stress group was placed in PVC cylinders (2.5 cm in diameter and 20 cm in length) for one hour/day until the 15th day of pregnancy. The female F1 offspring was nursed by their mothers until reaching 25–30 g (9–10 weeks) which was tested for spatial memory, anxiety and depressive-like behavior using Barnes Maze, elevated plus-maze and forced swimming test, respectively. Also, the brain BDNF level was assessed by the ELISA method. Mice that underwent prenatal restraint stress exhibited impaired spatial memory in the Barnes Maze, which the time and distance to achieve the target hole and the number of errors in the female adult offspring increased than the control group. In the elevated plus-maze, the animals that underwent prenatal restraint stress spent less time in the open arms of the maze and reduced entering the open arms, compared to the control group. In addition, stress caused a significant decrease in swim time and a significant increase in float time for the female adult offspring compared to the control group. The brain BDNF concentration also decreased significantly in the stress group compared to the control group. This data suggests that prenatal stress may impair spatial memory and induce anxiety and depressive-like behavior in the adult offspring female mice via reducing brain BDNF.

According to several new cumulative evidences, erythropoietin can be a possibility for investigation as a different therapeutic agent in neuropsychiatric diseases. This is as a result of its key role in neurotrophic effects. In order to understand the association, the gene expressions of EPO and EPO-R with bipolar mood disorder in peripheral blood mononuclear cells of some patients with bipolar I disorder in manic episode, were evaluated. In a case-control study, 22 patients with bipolar I disorder (single manic episode) and 22 healthy individuals were enrolled. All participants were above 15 years of age who were referred to Farshchian Hospital, Hamadan, Iran. They were diagnosed with bipolar type 1 in manic episode by a psychiatrist using DSM-IV-TR criteria and Young Mania Rating Scale (YMRS) in order to determine the severity of mania. The expressions of EPO and EPO-R genes in peripheral blood mononuclear cells were evaluated using Real-time RT-PCR analysis. The results showed a reduction in the gene expression of EPO (89.6%) and an increase in EPO-R (77.06%) in peripheral blood mononuclear cells (PBMCs) of the patients compared to the healthy controls. According to student paired samples T-test, there was statistically significant difference for each gene (p-value <0.001). This study shows that in patients with bipolar I mood disorders in manic episode, the expression of EPO and EPO-R gene can be employed in elucidating the pathogenesis of bipolar disorder.