Chronic stress is often a precursor to depression. Multiple brain mechanisms underlying the development of depression involve alterations in neurotrophin signaling. In the present study, male Wistar rats were exposed to chronic mild unpredictable stress (CMS), a well-known rodent model of depression, in order to investigate changes in BDNF content, BDNF mRNA expression, and BDNF receptor expression in different brain regions. After 8 weeks of CMS, anhedonia, a symptom of a depressive state, developed in 35% of stressed rats, while 65% remained resilient. The CMS treatment did not significantly affect the BDNF content as measured by ELISA in the frontal cortex, other neocortical regions, the hippocampus, and the medulla oblongata. The levels of exon I Bdnf mRNA decreased in the frontal cortex of both anhedonic and resilient rats. No changes were observed in exons IV, VI and IX in any of the studied brain structures, except for the hippocampus of anhedonic rats, where there was a tendency toward decreased exon IX Bdnf mRNA. The levels of Ntrk2 and Ngfr mRNAs did not significantly change in the brain after CMS. Therefore, the alterations in the expression of exon I Bdnf mRNA observed in this study were caused by chronic stress but were not associated with depression-like anhedonia.

BACKGROUND:Stroke is the most common cause of newly diagnosed epilepsy in the elderly, ahead of degenerative disorders, brain tumors, and head trauma. Stroke accounts for 30-50% of unprovoked seizures in patients aged ≥ 60 years. This review discusses the current understanding of epidemiology, risk factors, mechanisms, prevention, and treatment opportunities for post-stroke epilepsy (PSE). METHODS:We performed a literature search in the PubMed and Cochrane Library databases. The keywords "stroke, epilepsy", "stroke, seizure", "post-stroke seizure", "post-stroke epilepsy" were used to identify the clinical and experimental articles on PSE. All resulting titles and abstracts were evaluated, and any relevant article was considered. The reference lists of all selected papers and reference lists of selected review papers were manually analyzed to find other potentially eligible articles. RESULTS:PSE occurs in about 6% of stroke patients within several years after the event. The main risk factors are cortical lesion, initial stroke severity, young age and seizures in acute stroke period (early seizures, ES). Other risk factors, such as a cardioembolic mechanism or circulation territory involvement, remain debated. The role of ES as a risk factor of PSE could be underestimated especially in young age. Mechanism of epileptogenesis may involve gliosis scarring, alteration in synaptic plasticity, etc.; and ES may enhance these processes. Statins especially in the acute period of stroke are possible agents for PSE prevention presumably due to their anticonvulsant and neuroprotection effects. Antiepileptic drugs (AED) monotherapy is enough for seizure prevention in most cases of PSE; but no evidence was found for its efficiency against epileptic foci formation. The growing interest in PSE has led to a notable increase in the number of published articles each year. To aid in navigating this expanding body of literature, several tables are included in the manuscript. CONCLUSION:Further studies are needed for better understanding of the pathophysiology of PSE and searching the prevention strategies.

Background and objectivesPost-stroke epilepsy (PSE) is a significant concern in the elderly population, with stroke being a leading cause of epilepsy in this demographic. Several factors have shown consistent associations with the risk of developing PSE, including cortical lesions, initial stroke severity, younger age, and the occurrence of early seizures. The primary objectives of this study were two-fold: (1) to determine the incidence of PSE and (2) to identify the risk factors associated with PSE in a prospective cohort of post-stroke patients.MethodsA prospective single-hospital study was conducted, involving patients diagnosed with acute ischemic and hemorrhagic stroke. The patients were followed up for 2 years (or until death) from the time of admission. Data about seizure occurrence and recurrent stroke were collected. Kaplan–Meyer curves were used for the assessment of PSE incidence and mortality. Possible predictors of PSE and mortality were selected from between-group analysis and tested in multivariable regressions.ResultsOur study enrolled a total of 424 patients diagnosed with acute stroke. Among them, 97 cases (23%) experienced early post-stroke seizures, and 28 patients (6.6%) developed PSE. The cumulative risks of developing PSE were found to be 15.4% after hemorrhagic stroke and 8.7% after ischemic stroke. In multivariable fine and gray regression with competitive risk of death, significant predictors for developing PSE in the ischemic cohort were watershed infarction (HR 6.01, 95% CI 2.29–15.77, p < 0.001) and low Barthel index at discharge (HR 0.98, CI 0.96–0.99, p = 0.04). Furthermore, patients who eventually developed PSE showed slower recovery and presented a worse neurologic status at the time of discharge. The in-hospital dynamics of the National Institutes of Health Stroke Scale (NIHSS) were significantly worse in the PSE group compared to the non-PSE group (p = 0.01).DiscussionA higher proportion of cases experienced early seizures compared to what has been commonly reported in similar studies. Watershed stroke and low Barthel index at discharge were both identified as independent risk factors of PSE in ischemic strokes, which sheds light on the underlying mechanisms that may predispose individuals to post-stroke epilepsy after experiencing an ischemic stroke.

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.

Selective vulnerability or resilience to mood disorders is related to individual differences or personality. In the present study forced swim test (FST) was used as a tool for division of male rats according to their immobility behavior. The animals were subjected to a chronic unpredictable mild stress (CUS). Depressive-like behavior and modifications in brain neurotrophin system of were examined after CUS exposure. The low immobile (LI) and high immobile (HI) rats demonstrated elusive differences in expression of BDNF ExVI mRNA and TrkA mRNA which was higher in the hippocampus and frontal cortex, respectively, of HI rats as compared to LI animals. Exposure to CUS resulted in development of depressive-like phenotype and increased anxiety in both subgroups; however, immobility in FST specifically decreased in the initially HI animals. In hippocampus of stressed LI rats, the contents of total BDNF mRNA decreased. In hippocampus of stressed HI rats, the content of TrkA mRNA increased whereas in frontal cortex, the content of BDNF exon I mRNA decreased in both LI and HI rats. The levels of BDNF ExIX and ExI as well TrkB mRNAs were higher in the hippocampus of HI rats as compared to LI rats. In general, the response of hippocampus to CUS was much more expressed as compared to frontal cortex. Thus, initially different stress coping strategies of rats in the FST (HI, LI) were associated with the development of similar behavioral phenotypes after chronic unpredictable stress; however, these phenotypes were associated with different alterations in neurotrophin systems of the brain.

The dorsal and ventral parts of the hippocampus are functionally and morphologically nonidentical, and differences include stress reactivity. The present report describes the first study of the influence of proinflammatory stress induced by administration of lipopolysaccharide on the functional state and levels of the stress hormone corticosterone and proinflammatory cytokines in the dorsal (DH) and ventral (VH) hippocampus as compared with the neocortex, as well as changes in blood levels. The DH and VH responded specifically to proinflammatory stress: neurological inflammation developed more quickly in the DH, while corticosterone accumulation occurred more quickly in the neocortex and VH; functionally (in terms of the state of synaptic plasticity and the phenomenon of in vivo long-term potentiation), the DH suffered first, impairments then spreading to the VH.

The dorsal and ventral parts of hippocampus are different both functionally, and morphologically; they also differ in stress reactivity. In this paper, we for the first time report the data on the effects of lipopolysaccharide-induced pro-inflammatory stress on the functional state, levels of stress hormone corticosterone and expression of pro-inflammatory cytokines in the dorsal (DH) and ventral hippocampus (VH) as compared with the neocortex and changes in blood. DH and VH specifically respond to the pro-inflammatory stress: neuroinflammation develops faster in DH, while corticosterone accumulation is evident in the neocortex and VH. Functionally (based on the state of synaptic plasticity according to in vivo long term potentiation), DH is affected foremost, later the changes are spreading to VH.

Most ischemic strokes are caused by the occlusion of the middle cerebral artery (MCAO), which results in focal brain lesions in different areas of the neocortex. Secondary damage develops in brain regions located out of the infarct area, including the hippocampus. Hippocampal lesion may lead to cognitive impairments and post-stroke depression. Here, we studied the time course of changes in the levels of corticosterone and proinflammatory cytokine interleukine-1β (IL-1β) in the blood and hippocampus of rats after transient focal brain ischemia. Activation of the hypothalamo–pituitary–adrenal axis, which causes a release of corticosterone into blood, was observed at the early stage after MCAO and was accompanied by the presence of the stress hormone in the hippocampi of both the ischemic and contralateral hemispheres. We show for the first time that this effect was observed only in the ventral hippocampus (VH) but not in the dorsal hippocampus (DH). MCAO induced accumulation of the proinflammatory cytokine IL-1β, which coexisted with the elevated level of corticosterone at the early and delayed stages after reperfusion and was also observed in the VH of both hemispheres. Our data show that the VH is more vulnerable to remote damage induced by MCAO compared to the DH and corticosteroid response and neuroinflammation may be detected in the VH of both ischemic and contralateral hemispheres.

Early postnatal proinflammatory stress may evoke behavioral impairments in adulthood; however, the underlying mechanisms are still elusive. The brain-derived neurotrophic factor (BDNF) plays a key role in neuroplastic changes in health, as well as in pathology. The BDNF gene is transcribed to exon-specific mRNAs and the pattern of their expression depends on stimulus. We suggested that disturbances of the exonspecific BDNF mRNA expression in the brain regions after stress induced by proinflammatory stimuli in the early postnatal period could be one of the underlying mechanisms of consequent behavioral impairments. Thus, the aim of the study was to examine the effects of proinflammatory stress in early postnatal ontogeny on the BDNF polypeptide content and the patterns of expression of the BDNF gene in the neocortex and hippocampus of prepubertal male rats. The proinflammatory stress was induced by the subcutaneous administration of bacterial lipopolysaccharide (LPS) to rat pups on postnatal days 3 and 5, while BDNF expression was studied in 36-day-old rats. The BDNF polypeptide content was estimated using an enzyme-linked immunosorbent assay, while a quantitative polymerase chain reaction followed by reverse transcription was used to detect the exon-specific BDNF mRNA expression. The levels of BDNF and its transcripts, containing the common exon IX were similar in the control and LPS-treated rats. In the rats treated with LPS, the level of BDNF mRNA containing exon IV was lower in the neocortex but not in the hippocampus. No changes in the expression of the transcripts containing exons I and VI were observed in any of the brain structures studied. We suggest that specific alterations in BDNF expression may be involved in susceptibility to the development of behavioral impairments of animals subjected to early proinflammatory stress.

Infectious diseases in early postnatal ontogenesis can induce neuroinflammation, disrupt normal central nervous system development, and contribute to pathogenesis of cerebral pathologies in adults. To study long-term consequences of such early stress, we induced neonatal proinflammatory stress (NPS) by injecting bacterial lipopolysaccharide into rat pups on postnatal days 3 and 5 and then assessed the levels of corticosterone, proinflammatory cytokines and their mRNAs, and neurotrophins and their mRNAs in the hippocampus and neocortex of the one-month-old animals. Long-term potentiation (LTP) was studied in hippocampal slices as an index of synaptic plasticity. NPS-induced impairments of LTP were accompanied by the accumulation of corticosterone and IL-6 in the hippocampus. In the neocortex, a decrease in exon IV BDNF mRNA was detected. We suggest that excessive corticosterone delivery to hippocampal receptors and proinflammatory changes persisting during brain maturation are among the principal molecular mechanisms responsible for NPS-induced neuroplasticity impairments.

Background: Aging is associated with some cognitive decline and enhanced risk of development of neurodegenerative diseases. It is assumed that altered metabolism and functions of neurotrophin systems may underlie these age-related functional and structural modifications. Cerebrolysin(TM) (CBL) is a neuropeptide mixture with neurotrophic effects, which is widely used for the treatment of stroke and traumatic brain injury patients. It is also evident that CBL has an overall beneficial effect and a favorable benefit-risk ratio in patients with dementia. However, the effects of CBL on cognition and brain neurotrophin system in normal aging remain obscure. Objective: The aim of the present study was to examine the age-related modifications of endogenous neurotrophin systems in the brain of male Wistar rats and the effects of CBL on learning and memory as well as the levels neurotrophins and their receptors. Methods: Old (23-24 months) and young (2-3 months) male Wistar rats were used for the study. A half of animals were subjected to CBL course (2.5 ml/kg, 20 i.p. injections). Behavior of rats was studied using the open field test and simple water maze training. The contents of NGF and BDNF were studied using enzyme-linked immunosorbent assay; the expression of neurotrophin receptors was estimated by Western-blot analysis. Results: CBL treatment did not affect general status, age-related weight changes, general locomotor activity as well as general brain histology. In a water maze task, a minor effect of CBL was observed in old rats at the start of training and no effect on memory retention was found. Aging induced a decrease in neurotrophin receptors TrkA, TrkB, and p75NTR in the neocortex. CBL counteracted effects of aging on neocortical TrkA and p75NTR receptors and decreased expression of proNGF without influencing overall NGF levels. BDNF system was not significantly affected by CBL. Conclusion: The pro-neuroplastic "antiaging" effects of CBL in the neocortex of old animals were generally related to the NGF rather than the BDNF system.

Free-radical-mediated processes are involved in a variety of physiological events, while oxidative stress and related redox deregulation are implicated in various pathological events. Tripeptide glutathione plays an important role in the antioxidant defense of the brain, particularly in the maintenance of the optimal redox state in neurons and glial cells. We studied the combined effects of pantothenic acid derivatives, pantothenol and calcium pantothenate, and memantine, which is a glutamate receptor antagonist that is widely used for the treatment of dementia, on amnesia induced by scopolamine in rats. Scopolamine induced amnesia in rats; however, unexpectedly, this effect was even more expressed in the memantine-pretreated animals. Memory impairments were less manifested in the rats that were pretreated with memantine in combination with panthenol or calcium pantothenate. The detrimental scopolamine effect on memory was accompanied by significant depletions of glutathione and coenzyme A in the brain. While memantine recovered the glutathione status to some extent, it nevertheless further aggravated the scopolamine influence on coenzyme A levels. An alleviation of scopolamine-induced memory impairments that was observed after combined pretreatment with memantine and panthenol or calcium pantothenate was accompanied by a normalization of coenzyme A levels, while the effects on glutathione redox did not correlate with the behavioral data.

Depression is the most common form of mental disability in the world. Depressive episodes may be precipitated by severe acute stressful events or by mild chronic stressors. Studies on the mechanisms of depression require both appropriate experimental models (most of them based on the exposure of animals to chronic stressors), and appropriate tests for assessment of depressive states. In this study male Wistar rats were exposed to two different chronic stress paradigms: an eight-week chronic unpredictable mild stress or a two-week combined chronic stress. The behavioral effects of stress were evaluated using sucrose preference, forced swim and open field tests. After the exposure to chronic unpredictable mild stress, anhedonia was developed, activity in the open field increased, while no changes in the duration of passive floating could be detected. After chronic combined stress, anhedonia was also evident, whereas behavior in the open field and forced swim test did not change. The levels of corticosterone in the blood and brain structures involved in stress-response did not differ from control in both experiments. The absence of significant changes in corticosterone levels and passive floating may be indicative of the adaptation of animals to chronic stress. Anhedonia appears to be a more sensitive indicator of depressive-like behavioral effects of chronic stress as compared to behavior in the forced swim or open field tests.

In experiments with animals, a group that is injected with the vehicle in which a drug of interest is dißsolved is often used as a control. However, even a single injection of a vehicle is a stressor, i.e., “treatment stress,” which may significantly affect some stress-sensitive indices. In the present study, we report some data on the effects of a single intraperitoneal injection of isotonic saline solution on the contents of corticosterone, nitric oxide metabolites, and oxidative capacity, as well as on the expression of proteins and mRNAs of proinflammatory cytokines in the blood and brain regions of rats within one day after the injection as compared to intact animals. At the early time points after the injection, corticosterone contents were substantially elevated in the blood and ventral hippocampus. The content of nitric oxide metabolites decreased in the blood and remained stably low within 2–24 h after the injection. The injection did not affect the contents of proinflammatory cytokines in the blood; however, early after the injection the expression of IL-1ß mRNA decreased in the ventral hippocampus and frontal cortex, whereas 24 h after this treatment, the expression of TNF-a mRNA increased by a factor of 4 in the frontal cortex. Thus, a single injection of isotonic saline solution had a clear stress-producing effect, which was observed at the systemic level and in stress-sensitive brain regions. The strength of this stressful event was sufficient to activate the hypothalamus–pituitary–adrenal axis but not sufficient to induce a significant inflammatory response. The frontal cortex was most sensitive to this treatment; the alterations in the ventral hippocampus were less expressed, whereas the dorsal hippocampus was most stress resistant. Our data show that it is important to consider and thoroughly analyze the effects of “treatment stress” in experiments using injections of biologically active substances.

Effects of neonatal proinflammatory stress (NPS) on the development of anxiety and depressive-like behavior, stress responsiveness, hippocampal plasticity and conditioned fear response were studied in adolescent and adult male Wistar rats. On PND 3 and PND 5, the pups were subcutaneously injected with bacterial lipopolysaccharide (LPS, 50 μg/kg). In the open field test, signs of increased anxiety were demonstrated in adolescent (PND 32), but not in adult (PND 101) rats. In the elevated plus maze, no changes could be detected in adolescent rats, however, in the adults the number of entries into the open arms decreased suggesting increased anxiety after NPS. Signs of "behavioral despair" in the forced swim test, expressed in adolescent rats as a trend, became significant in the adults indicating depression-like behavior. In the majority of brain slices from PND 19-PND 33 rats subjected to NPS, deficit of LTP in the hippocampal CA1 field was detected, this deficit being associated with the impaired mechanisms of LTP induction. In the adult rats, NPS enhanced fear conditioning promoting improved formation of the novel context-foot shock association in the contextual fear conditioning paradigm without effect on cued fear conditioning. NPS significantly impaired functioning of the hypothalamic-pituitary-adrenal axis (HPAA), resulting in an elevated corticosterone level maintained in the adolescents but not in the adults and in modified corticosterone response to behavioral sub-chronic stress in both adolescent and adult rats. Thus, NPS induces "perinatal malprogramming" resulting in development of depression-like behaviors, associated with abnormalities in functioning of the HPAA, impaired hippocampal neuroplasticity (LTP) and changes in hippocampus-dependent memory formation.

Тревожно-депрессивные расстройства относятся к наиболее распространенным психическим патологиям. Актуальная стресс-реактивность является важным параметром, характеризующим текущее состояние пациентов, потенциально – перспективу и эффективность их излечения. В связи с этим важной задачей является поиск простых, доступных для клинического применения тестов, позволяющих оценить стресс-реактивность. В данной статье представлены данные пилотного исследования, направленного на поиск маркеров стресс-реактивности у пациентов с тревожно-депрессивной симптоматикой (ТДС). Кровь пациентов анализировали до и после психоэмоционального стресс-теста. Полученные результаты сравнивали с данными, полученными на крысах с депрессивноподобным поведением, которых также подвергали стрессорной нагрузке. После стресс-теста уровень глюкозы в крови достоверно возрастал как у пациентов с ТДС, так и у животных с депрессивноподобным поведением. Примененные стрессорные нагрузки не вызывали таких изменений у здоровых людей и животных контрольной группы. Таким образом, умеренный стресс-тест и анализ глюкозы в крови – валидный подход, позволяющий оценить стресс-реактивность как в экспериментальных, так и в клинических исследованиях.