Vol 12, No 3 (2018)

This review discusses the current experimental data on targeted drug delivery through the blood–brain barrier (BBB). We focus on exosome drug delivery and examine the unique biological structure of exosomes, which allows them to pack, store, and deliver various molecules to the brain. Various approaches to modification and engineering of exosomes are reviewed with an analysis of experimental studies of exosome drug delivery through the BBB. The problems associated with potential clinical uses of exosomes and their possible solutions are discussed.

Intelligence is the core construct of behavioral genetics studies and is one of the most heritable behavioral traits. Molecular genetics studies attempt to identify the genes which are responsible for the levels of intelligence and its heritability. In order to understand the main signaling and biochemical pathways that are involved in intelligence, functional genomics could be applied. Herein, we selected a total of 181 intelligence- related genes (IRGs), selected from genome-wide association studies and literatures, to incorporate these genes in related signaling pathways, aiming to understand the underlying biological mechanisms. Disregarding the tissue types, computational pathway analyses demonstrated that IRGs were mostly enriched in the Wnt signaling pathway. Nevertheless, pathway enrichment of brain-specific IRGs, highlighted the role of G-protein- and dopamine-mediated signaling pathways. These findings represent a comprehensive and assembled intracellular molecular network for intelligence. It is of great importance to identify RNA or protein molecules, responsible for regulation of these signaling pathways.

The molecular changes in the glutamatergic system of the rat amygdala were studied during the latent phase of the lithium–pilocarpine model of temporal lobe epilepsy in order to identify the potential involvement of these changes in epileptogenesis. The real-time PCR method was used to evaluate the mRNA expression of the NMDA and AMPA receptor subunits, as well as the excitatory amino acid transporter-2 (EAAT2) in the basolateral nucleus of the amygdala 7 days after the seizures caused by administration of pilocarpine. The results of the experiments were as follows: (1) an increase in the expression ratio of the GluN2a/GluN2b NMDA receptor subunits with an unchanged expression level of the GluN1 subunit; (2) increased expression of the GluA2 subunit of AMPA receptors with the invariance of GluA1, and (3) enhanced expression of the EAAT2. According to literature data, the expression of the same genes decreased in the hippocampus in the same model of epilepsy. Neurodegeneration was reported in both brain regions. The opposite changes in the expression of the glutamatergic system genes in the hippocampus and amygdala during the latent period of the lithium–pilocarpine model suggest the occurrence of factors that can both contribute to and hinder epileptogenesis.

Recent studies imply that epigenetic mechanisms may play a key role in the pathogenesis of severe neurological diseases. We have previously shown that acetylation of histone H3 at Lys 24 (H3acK24) is involved in the formation of acute adaptive response of the brain to hypoxia. Here, using an immunohistochemical technique, we compared the effects of severe hypoxia and severe hypoxia followed by neuroprotective postconditioning using mild hypoxia on the expression of the antiapoptotic Bcl-2 protein, neurotrophin BDNF, and the level of H3acK24 in the neocortex of rats in delayed period (4 days). The delayed upregulation of Bcl-2, BDNF, and H3acK24 was observed in the sensorimotor cortex of rats subjected to severe hypoxia, suggesting late induction of the pro-adaptive neuronal processes. Postconditioning by three episodes of mild hypoxia returned the levels of H3acK24 to the control level and partially abolished the upregulation of Bcl-2 and BDNF. The findings demonstrate an important role of H3 acetylation at Lys24 in the regulation of apoptosis and neuroplasticity in response to hypoxia.

To evaluate the consequences of traumatic brain injury (TBI), we used a model of lateral fluid percussion brain injury in freely moving male Wistar rats. The immediate response to TBI included development of motor excitation and tonic–clonic seizures. Morphological analysis was performed 7 day after TBI. To localize IgG in the brain, rat brain slices were double stained with antibodies against IgG and NeuN (neuronal marker). To evaluate the state of microglia, we performed staining with Isolectin B4 (a microglial marker). The number of neurons was measured in sections stained using the Nissl method. The results show the IgG accumulation in neurons adjacent to cortical focus of trauma. In the hippocampus, IgG was accumulated in the neurons of the ipsilateral hippocampal CA1 and CA2 fields and the dentate gyrus, while in the contralateral hemisphere IgG was accumulated in the neurons of the CA1 field. These changes were accompanied by activation of microglia in the hippocampus, as well as by a decrease in neuronal density in the dentate gyrus of the ipsilateral hippocampus. The results show that TBI leads to bilateral damage to the hippocampus.

The pathogenesis of borderline personality disorders remains obscure. Depression is one of most common representatives of this group of diseases. Recently, we showed that the development of depression is accompanied by specific changes in the immune system. In the lymphocytes of patients with depression, the activities of apoptotic proteases of caspase family increase with increasing severity of depression, which may be indicative of augmented death of these cells [1]. Our goal was to explore the mechanisms of activation of caspases in this situation and study the expression of caspase family proteins in lymphocytes of patients with depression. Changes in the activity of caspase family enzymes in the lymphocytes of patients with depression were not accompanied by alterations in the expression of the respective proteins. Thus, in depression, the mechanism of lymphocyte caspase activity control is disturbed, but not expression of caspases.

Many studies are focused on the mechanisms of CNS formation, especially on the molecular bases of CNS functioning at different stages of maturation. It is known that functional maturation of different parts of the neocortex occurs at different time points of postnatal ontogeny and gap junctions play an important role in this process. So far, it was not clear whether the expression of major proteins that form gap junctions, connexins, is uniform in the neocortex during its maturation. We compared the dynamics of mRNA level of connexin-30 (Cx30, gjb6) and connexin-32 (Cx32, gjb1) in the somatosensory and visual parts of the neocortex during period of early postnatal ontogeny. We measured the mRNA level of mentioned connexins using quantitative real-time PCR after reverse transcription in the samples of neocortex collected at postnatal days 5, 8, 10, 13, and 20. We found that the level of Cx30 mRNA progressively increased in the somatosensory neocortex from the 5th to 20th day of postnatal ontogeny. In contrast, the level of Cx30 mRNA in the visual cortex began to increase only after the 10th day of postnatal development. Analysis of Cx32 expression showed that its expression started to increase only after 10th day in the somatosensory cortex and after 13th day in the visual cortex. Taken together, our data suggest that the expression of Cx30 and Cx32 is more intense in the somatosensory than in the visual neocortex at early stages of ontogeny which may reflect different time course of maturation of these neocortical areas.