Neuronal Exosomes as a New Signaling System.

Number of studies devoted to investigation of neuronal exosomes increases significantly each year. Potential of exosomes as diagnostic markers of neurodegenerative diseases has been examined thoroughly and similar protocols were used to search for the markers of other psychiatric disorders. Biogenesis of exosomes in various types of cells has been studied, physiological role of exosomes has been actively investigated, and many features of their signaling cascades have been clarified. The accumulated data indicate important role of the exosome signaling in interneuronal communication. Do we have enough grounds to recognize exosomes as new non-canonical neurotransmitters in the brain? In this review we discuss this issue and present a concept on the possible role of brain exosomes as a new signaling system to the scientific community.

Development of Post-Stroke Cognitive and Depressive Disturbances: Associations with Neurohumoral Indices.

Neuropsychiatric complications, in particular cognitive and depressive disorders, are common consequences of ischemic stroke (IS) and complicate the rehabilitation, quality of life, and social adaptation of patients. The hypothalamic-pituitary-adrenal (HPA) system, sympathoadrenal medullary system (SAMS), and inflammatory processes are believed to be involved in the pathogenesis of these disorders. This study aimed to explore these systems in IS patients, including those with post-stroke cognitive and depressive disorders, within a year after IS. Indices of the HPA axis, inflammatory system, and SAMS were measured in blood serum (cortisol, interleukin-6 (IL-6)), plasma (adrenocorticotropic hormone), and saliva (cortisol, α-amylase). During one year after mild/moderate IS (NIHSS score 5.9 ± 4.3), serum cortisol and salivary α-amylase levels remained elevated in the total cohort. In the group with further cognitive decline, serum and salivary cortisol levels were elevated during the acute period of IS. In the group with poststroke depressive disorder, salivary α-amylase was constantly elevated, while serum IL-6 was minimal during the acute period. The results suggest prolonged hyperactivation of the HPA axis and SAMS after IS. Specifically, post-stroke cognitive impairment was associated with hyperactivation of the HPA axis during the acute IS period, while post-stroke depressive disorder was associated with the chronic inflammatory process and hyperactivation of SAMS during the follow-up period.

Elevated Serum Cortisol Levels in Patients with Focal Epilepsy, Depression, and Comorbid Epilepsy and Depression.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes and neurotrophic factor systems are involved in pathogenesis of both epilepsy and depressive disorders. The study aimed to explore these systems in patients with focal epilepsy (PWE, n = 76), epilepsy and comorbid depression (PWCED n = 48), and major depressive disorder (PWMDD, n = 62) compared with healthy controls (HC, n = 78). METHODS: Parameters of the HPA axis, neurotrophic factors, and TNF-α were measured in blood serum along with the hemogram. RESULTS: Serum cortisol level was augmented in PWE, PWCED, and PWMDD compared with HC and was higher in PWMDD than in PWE. Serum cortisol negatively correlated with Mini-Mental State Examination (MMSE) score in PWE, and positively with depression inventory-II (BDI-II) score in PWMDD. Only PWMDD demonstrated elevated plasma ACTH. Serum TNF-α, lymphocytes, and eosinophils were augmented in PWMDD; monocytes elevated in PWE and PWCED, while neutrophils were reduced in PWE and PWMDD. Serum BDNF was decreased in PWE and PWCED, CNTF was elevated in all groups of patients. In PWE, none of above indices depended on epilepsy etiology. CONCLUSIONS: The results confirm the involvement of HPA axis and inflammatory processes in pathogenesis of epilepsy and depression and provide new insights in mechanisms of epilepsy and depression comorbidity.

Fluorescence Lifetime and Intensity of Thioflavin T as Reporters of Different Fibrillation Stages: Insights Obtained from Fluorescence Up-Conversion and Particle Size Distribution Measurements.

Thioflavin T (ThT) assay is extensively used for studying fibrillation kinetics in vitro. However, the differences in the time course of ThT fluorescence intensity and lifetime and other physical parameters of the system, such as particle size distribution, raise questions about the correct interpretation of the aggregation kinetics. In this work, we focused on the investigation of the mechanisms, which underlay the difference in sensitivity of ThT fluorescence intensity and lifetime to the formation of protein aggregates during fibrillation by the example of insulin and during binding to globular proteins. The assessment of aggregate sizes and heterogeneity was performed using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Using the sub-nanosecond resolution measurements, it was shown that the ThT lifetime is sensitive to the appearance of as much as a few percent of ThT bound to the high-affinity sites that occur simultaneously with an abrupt increase of the average particle size, particles concentration, and size heterogeneity. The discrepancy between ThT fluorescence intensity and a lifetime can be explained as the consequence of a ThT molecule fraction with ultrafast decay and weak fluorescence. These ThT molecules can only be detected using time-resolved fluorescence measurements in the sub-picosecond time domain. The presence of a bound ThT subpopulation with similar photophysical properties was also demonstrated for globular proteins that were attributed to non-specifically bound ThT molecules with a non-rigid microenvironment.

Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent.

Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10-100 mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect TrkB protein levels as well as its phosphorylation status, inhibition of NO synthesis decreased levels of phosphorylated TrkB after withdrawal. Thus, NO signaling during induction of dependence may be involved in the mechanisms of BDNF expression and processing at abstinence, thereby affecting signaling through TrkB in the frontal cortex.

Factors associated with lifetime history of eating disorder in non-psychotic patients with suicidal ideation.

BACKGROUND: Data on the sociodemographic, biographical, and clinical factors associated with a lifetime diagnosis of eating disorders (ED) in patients with non-psychotic mental disorders (NPMD) and suicidal ideation (SI) are scarce. METHODS: A cohort study was conducted at the Moscow Research and Clinical Center for Neuropsychiatry. The sample consisted of consecutive patients with non-psychotic mental disorders and SI, aged 1845 years. Participants with a lifetime diagnosis of anorexia and/or bulimia (then in remission or recovery) were compared with those without ED in terms of their sociodemographic profile, clinical characteristics, lifetime traumatic events, and some behavioral patterns. All participants underwent the Russian version of the Self-Injurious Thoughts and Behaviors Interview and completed the Brief Reasons for Living Inventory, the State and Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 892 patients with non-psychotic mental disorders and SI were included in the study. The mean age was 25.7 years, and 84% were assigned female at birth. Same-sex experience was more common in the ED group. Patients with an ED were more likely to have a history of physical and sexual abuse and to have witnessed domestic violence. The proportion of participants with piercings, tattoos, or severe body modifications was significantly higher in the ED group. Patients with a lifetime ED were more likely to engage in nonsuicidal self-injurious behaviors and to have a history of suicide attempts. CONCLUSION: Lifetime ED in NPMD patients with SI is associated with younger age, being assigned female at birth, having an alternative gender identity, having same-sex experience, having more than one psychiatric diagnosis, having been diagnosed with bipolar disorder, experiencing severe depression and anxiety, being exposed to multiple traumatic experiences, having various body modifications, practicing NSSI, and having a lifetime story of suicide attempts.

Amyloid-beta (25-35) increases activity of neuronal NO-synthase in rat brain.

Nitric oxide (NO) is a free radical with multiple functions in the nervous system. NO plays an important role in the mechanisms of neurodegenerative diseases including Alzheimer's disease. The main source of NO in the brain is an enzymatic activity of nitric oxide synthase (NOS). The aim of the present study was to analyze the expression and activity of both neuronal (nNOS) and inducible (iNOS) isoenzymes in the cerebral cortex and hippocampus of rats after intracerebroventricular administration of amyloid-beta (A beta) peptide fragment A beta(25-35). NADPHd histochemistry as well as immunohistochemistry were also used to investigate nNOS and iNOS expression in rat brain. The data presented here show that A beta(25-35) did not influence levels of nNOS or iNOS mRNA or protein expression in both structures studied. A beta(25-35) activated nNOS in the cerebral cortex and hippocampus without effect on iNOS activity. A beta(25-35) decreased the number of NADPHd-expressing neurons in the neocortex, but it did not significantly influence the number NADPHd-positive cells in the hippocampus. The peptide had no effect on the number of nNOS containing cells. We hypothesize that increased synthesis of NO induced by A beta(25-35) is related to qualitative alterations of nNOS molecule, but not to changes in NOS protein expression.

Increased S-nitrosothiols are associated with spinal cord injury in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disorder associated with inflammation, demyelination and axonal damage. In search of potential biomarkers of spinal cord lesions in MS related to nitric oxide metabolites, we measured total nitrite and nitrate levels, and protein-bound nitrotyrosine and S-nitrosothiol concentrations in the serum of MS patients at different stages of the disease. Sixty-eight patients and 36 healthy volunteers were included in the study. Total nitrite and nitrate levels were augmented in relapsing-remitting MS, while increased S-nitrosothiol concentrations were found both in relapsing-remitting and secondary-progressive MS. Further analysis demonstrated that S-nitrosothiol levels were selectively increased in patients with spinal cord injury. The data suggest that high S-nitrosothiol concentration may be a potential serum biomarker for spinal cord injury in MS.

Footshock stress alters early postnatal development of electrophysiological responses and caspase-3 activity in rat hippocampus.

Postnatal changes in population spike (PS) amplitudes and caspase-3 activity were compared in the hippocampi of control rats and experimental animals subjected to a brief footshock on postnatal day (PD) 13. Footshock induced an increase in maximal PS amplitudes during the early period (from PD 14 to PD 16), however, the difference between stressed and control animals gradually decreased with age up to PD 21. No difference between hippocampal caspase-3 activity in control and footshock groups was revealed within the PD 14-17. However, caspase-3 activity in the latter group was significantly lower over the next period of postnatal development (PD 18-21). PS amplitudes in the slices of the footshock group significantly increased over PD 22-27. We suggest that footshock activates the development of hippocampal circuitry during early phases, this phenomenon mediating enhanced responsiveness as a result of an increased production of synaptic connections and related decrease in neuronal loss.

Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25-35).

Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18 microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of 0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated animals). Seven days after the surgery brain sections were stained with cresyl violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP) and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain regions was measured fluorometrically. The morphology of the hippocampus after the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Abeta(25-35)-treated groups compared to the contralateral hemisphere of both vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha augmented the Abeta(25-35)-induced damage, significantly increasing the extension of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and the presence of hypertrophic astrocytes in the hippocampus. This effect was much more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but absent after administration of TNFalpha alone. In both Abeta(25-35)-treated groups, the damaged area of the hippocampal CA1 field and lateral band of dentate gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the control brain sections or in brain sections of TNFalpha-injected animals. The activity of caspase-3 increased significantly in the ipsilateral hippocampus after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha into the cerebral ventricles prevented this Abeta(25-35)-induced increase in hippocampal caspase-3 activity. The results are discussed from the perspective of dual (neuroprotective and neurodestructive) roles of TNF in the brain.