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The review analyzes modern concepts about the control of various mechanisms of the hippocampal neuroplasticity in adult mammals and humans by glucocorticoids. Glucocorticoid hormones ensure the coordinated functioning of key components and mechanisms of hippocampal plasticity: neurogenesis, glutamatergic neurotransmission, microglia and astrocytes, systems of neurotrophic factors, neuroinflammation, proteases, metabolic hormones, neurosteroids. Regulatory mechanisms are diverse; along with the direct action of glucocorticoids through their receptors, there are conciliated glucocorticoid-dependent effects, as well as numerous interactions between various systems and components. Despite the fact that many connections in this complex regulatory scheme have not yet been established, the study of the factors and mechanisms considered in the work forms growth points in the field of glucocorticoid-regulated processes in the brain and primarily in the hippocampus. These studies are fundamentally important for the translation into the clinic and the potential treatment/prevention of common diseases of the emotional and cognitive spheres and respective comorbid conditions. [ABSTRACT FROM AUTHOR]

The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders. [ABSTRACT FROM AUTHOR]

A comprehensive overview of the interplay between glucocorticoids (GCs) and adult hippocampal neurogenesis (AHN) is presented, particularly, in the context of a diseased brain. The effectors of GCs in the dentate gyrus neurogenic niche of the hippocampal are reviewed, and the consequences of the GC signaling on the generation and integration of new neurons are discussed. Recent findings demonstrating how GC signaling mediates impairments of the AHN in various brain pathologies are overviewed. GC‐mediated effects on the generation and integration of adult‐born neurons in the hippocampal dentate gyrus depend on the nature, severity, and duration of the acting stress factor. GCs realize their effects on the AHN primarily via specific glucocorticoid and mineralocorticoid receptors. Disruption of the reciprocal regulation between the hypothalamic–pituitary–adrenal (HPA) axis and the generation of the adult‐born granular neurons is currently considered to be a key mechanism implicating the AHN into the pathogenesis of numerous brain diseases, including those without a direct hippocampal damage. These alterations vary from reduced proliferation of stem and progenitor cells to increased cell death and abnormalities in morphology, connectivity, and localization of young neurons. Although the involvement of the mutual regulation between the HPA axis and the AHN in the pathogenesis of cognitive deficits and mood impairments is evident, several unresolved critical issues are stated. Understanding the details of GC‐mediated mechanisms involved in the alterations in AHN could enable the identification of molecular targets for ameliorating pathology‐induced imbalance in the HPA axis/AHN mutual regulation to conquer cognitive and psychiatric disturbances. [ABSTRACT FROM AUTHOR]

Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia. [ABSTRACT FROM AUTHOR]

This Editorial highlights a remarkable study in the current issue of the Journal of Neurochemistry in which Hascup and coworkers provide novel data showing that riluzole, an anti‐glutamatergic drug, may be a promising early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to amyloid beta (Aβ) plaque accumulation and cognitive decline. The mice APP/PS1, a model of AD, initially are cognitively normal but have elevated glutamate release in the hippocampus at 2–4 months of age. They begin showing cognitive decline and Aβ plaque accumulation at approximately 6–8 months of age, and show obvious AD neuropathology and cognitive impairment at 10–12 months. The riluzole treatment over 4 months (at 2–6 months of age) targeting early changes in glutamatergic neurotransmission prevents cognitive decline observed at 12 months of age and restores glutamatergic neurotransmission. This is one of the most convincing preclinical evidence supporting the idea of targeting glutamate neurotransmission in patients at risk for AD and to use riluzole for this purpose. [ABSTRACT FROM AUTHOR]

The hippocampus is not a homogeneous brain area, and the complex organization of this structure underlies its relevance and functional pleiotropism. The new data related to the involvement of the ventral hippocampus in the cognitive function, behavior, stress response and its association with brain pathology, in particular, depression, are analyzed with a focus on neuroplasticity, specializations of the intrinsic neuronal network, corticosteroid signaling through mineralocorticoid and glucocorticoid receptors and neuroinflammation in the hippocampus. The data on the septo-temporal hippicampal gradient are analyzed with particular emphasis on the ventral hippocampus, a region where most important alteration underlying depressive disorders occur. According to the recent data, the existing simple paradigm "learning (dorsal hippocampus) versus emotions (ventral hippocampus)" should be substantially revised and specified. A new hypothesis is suggested on the principal involvement of stress response mechanisms (including interaction of released glucocorticoids with hippocampal receptors and subsequent inflammatory events) in the remote hippocampal damage underlying delayed dementia and depression induced by focal brain damage (e.g. post-stroke and post-traumatic). The translational validity of this hypothesis comprising new approaches in preventing post-stroke and post-trauma depression and dementia can be confirmed in experimental and clinical studies. [ABSTRACT FROM AUTHOR]

A simple tongue protrusion (TP) test is described for rats following focal ischemia induced by middle cerebral artery occlusion (MCAO). MCAO resulted in a dramatic decrease in TP that correlated with a concomitant decline in neurological performance in standard 5- and 20-point tests and deficits in performance in the Morris water maze and the accelerating rotarod. TP values also correlated with infarct size at 7 and 24 days following MCAO. This simple and inexpensive test, that monitors the ability of rats to lick food out of a glass tube, is easily administered, can be administered frequently without changing baseline performance, is not susceptible to behavioral compensation and should not interfere with other tests used concurrently to evaluate neurological deficit. The TP test may, therefore, serve as a useful addition to the battery of tests commonly used to assess neurological damage in rats, particularly in models of stroke. [Copyright &y& Elsevier]

Read the full article ‘Deletion of Atf6α impairs astroglial activation and enhances neuronal death following brain ischemia in mice’ on page 342. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) mediates opiate dependence phenomenon. In the brain of morphine dependent animals BDNF level is controlled transcriptionally, however, post-transcriptional mechanisms of BDNF regulation in this context remain unknown. Regulation of mRNA by binding of specific proteins to the 3'-untranslated region (3′-UTR) is one of such mechanisms. Among RNA-binding proteins neuronal Hu antigen D (HuD) is the best characterized positive regulator of BDNF, however its involvement in opiate dependence remains obscure. We suggested that HuD binding to the BDNF 3′-UTR may be linked to changes in BDNF expression induced by morphine. The aim of this study was to investigate potential association of HuD with BDNF 3′-UTR in relation to BDNF expression (Exon- and 3′-UTR-specific mRNA variants and protein level) in the frontal cortex and midbrain of male Wistar rats after chronic morphine intoxication and spontaneous withdrawal in dependent animals. After chronic morphine intoxication but not during morphine withdrawal HuD binding to the long BDNF 3′-UTR in the frontal cortex decreased as compared with the corresponding control group, however after intoxication BDNF expression did not change. The level of BDNF Exon I as well as mature BDNF polypeptide increased in the frontal cortex upon morphine withdrawal, while no changes in HuD binding could be detected. Thus, contrary to the assumption, HuD-BDNF 3′-UTR interaction and BDNF expression in the frontal cortex differentially change in a manner dependent on the context of morphine action. [ABSTRACT FROM AUTHOR]

Read the full article 'Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease' on doi: . [ABSTRACT FROM AUTHOR]

Ischemic brain injuries are accompanied by the long-term changes in gene expression in the hippocampus, the limbic system structure, involved in the regulation of key aspects of the higher nervous activity, such as cognitive functions and emotions. The altered expression of genes and proteins encoded by them may be related to the development of post-ischemic psycho-emotional and cognitive disturbances. Activation of neuroinflammation following stroke in the hippocampus has been suggested to play an essential role in induction of long-lasting consequences. Identification of changes in the gene expression patterns after ischemia and investigation of the dynamics of these changes in the hippocampus are the necessary first steps toward understanding molecular pathways responsible for the development of post-stroke cognitive impairments and mental pathologies. [ABSTRACT FROM AUTHOR]

Our previous studies showed that in patients with brain diseases, neurotrophic factors in lacrimal fluid (LF) may change more prominently than in blood serum (BS). Since glial cell line-derived neurotrophic factor (GDNF) is involved in the control of neuronal networks in an epileptic brain, we aimed to assess the GDNF levels in LF and BS as well as the BDNF and the hypothalamic–pituitary–adrenocortical and inflammation indices in BS of patients with focal epilepsy (FE) and epilepsy and comorbid depression (FE + MDD) and to compare them with those of patients with major depressive disorder (MDD) and healthy controls (HC). GDNF levels in BS were similar in patients and HC and higher in FE taking valproates. GDNF levels in LF were significantly lower in all patient groups compared to controls, and independent of drugs used. GDNF concentrations in LF and BS positively correlated in HC, but not in patient groups. BDNF level was lower in BS of patients compared with HC and higher in FE + MDD taking valproates. A reduction in the GDNF level in LF might be an important biomarker of FE. Logistic regression models demonstrated that the probability of FE can be evaluated using GDNF in LF and BDNF in BS; that of MDD using GDNF in LF and cortisol and TNF-α in BS; and that of epilepsy with MDD using GDNF in LF and TNF-α and BDNF in BS. [ABSTRACT FROM AUTHOR]

Brain aging is associated with a progressive decrease in learning abilities, memory, attention, decision making, and sensory perception. Age-related cognitive disturbances may be related to a decrease in the functional capacities of the hippocampus. This brain region is essential for learning and memory, and the lifelong neurogenesis occurring in the subgranular zone of the dentate gyrus may be a key event mediating the mnemonic functions of the hippocampus. In the present study, we investigated whether age-related changes in hippocampal neurogenesis are associated with learning and memory disturbances. Four- and 24-month-old rats were trained to find a hidden platform in a water maze. Though the older group showed higher latency to search the platform as compared to the younger group, both groups learned the task. However, the density of proliferating (PCNA-positive), differentiating (Dcx-positive), and new neurons (pre-labeled BrdU-positive) was significantly lower in the hippocampus of aged rats as compared to young ones. This inhibition of neurogenesis could be related to increased local production of nitric oxide since the density of neurons expressing neuronal NO-synthase was higher in the aged hippocampus. Thus, we can suggest that an age-related decrease in neurogenesis is not directly associated with place learning in aged rats. [ABSTRACT FROM AUTHOR]

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels. [ABSTRACT FROM AUTHOR]

The article presents information on the role of 9-methyl-β-carboline as a potential cognitive enhancer and a treatment of Parkinson's disease and other neurodegenerative diseases. It focuses on a study which includes experiments on the mechanisms and efficiency of the compound in correcting cognitive decline.

The possibility of epileptiform activity generation by the thalamocortical neuronal network after focal brain injuries, including traumatic brain injury (TBI), is actively debated. Presumably, posttraumatic spike–wave discharges (SWDs) involve a cortico-thalamocortical neuronal network. Differentiation of posttraumatic and idiopathic (i.e., spontaneously generated) SWDs is imperative for understanding posttraumatic epileptogenic mechanisms. Experiments were performed on male Sprague-Dawley rats with electrodes implanted into the somatosensory cortex and the thalamic ventral posterolateral nucleus. Local field potentials were recorded for 7 days before and 7 days after TBI (lateral fluid percussion injury, 2.5 atm). The morphology of 365 SWDs (89 idiopathic before craniotomy, and 262 posttraumatic that appeared only after TBI) and their appearance in the thalamus were analyzed. The occurrence of SWDs in the thalamus determined their spike–wave form and bilateral lateralization in the neocortex. Posttraumatic discharges were characterized by more "mature" characteristics as compared to spontaneously generated discharges: higher proportions of bilateral spreading, well-defined spike–wave form, and thalamus involvement. Based on SWD parameters, the etiology could be established with an accuracy of 75% (AUC 0.79). Our results support the hypothesis that the formation of posttraumatic SWDs involves a cortico-thalamocortical neuronal network. The results form a basis for further research of mechanisms associated with posttraumatic epileptiform activity and epileptogenesis. [ABSTRACT FROM AUTHOR]

Among the responses in the early stages of stroke, activation of neurodegenerative and proinflammatory processes in the hippocampus is of key importance for the development of negative post-ischemic functional consequences. However, it remains unclear, what genes are involved in these processes. The aim of this work was a comparative study of the expression of genes encoding glutamate and GABA transporters and receptors, as well as inflammation markers in the hippocampus one day after two types of middle cerebral artery occlusion (according to Koizumi et al. method, MCAO-MK, and Longa et al. method, MCAO-ML), and direct pro-inflammatory activation by central administration of bacterial lipopolysaccharide (LPS). Differences and similarities in the effects of these challenges on gene expression were observed. Expression of a larger number of genes associated with activation of apoptosis and neuroinflammation, glutamate reception, and markers of the GABAergic system changed after the MCAO-ML and LPS administration than after the MCAO-MK. Compared with the MCAO-ML, the MCAO-MK and LPS challenges caused changes in the expression of more genes involved in glutamate transport. The most pronounced difference between the responses to different challenges was the changes in expression of calmodulin and calmodulin-dependent kinases genes observed after MCAO, especially MCAO-ML, but not after LPS. The revealed specific features of the hippocampal gene responses to the two types of ischemia and a pro-inflammatory stimulus could contribute to further understanding of the molecular mechanisms underlying diversity of the post-stroke consequences both in the model studies and in the clinic. [ABSTRACT FROM AUTHOR]

Acute and chronic corticosterone (CS) elevations after traumatic brain injury (TBI) may be involved in distant hippocampal damage and the development of late posttraumatic behavioral pathology. CS-dependent behavioral and morphological changes were studied 3 months after TBI induced by lateral fluid percussion in 51 male Sprague–Dawley rats. CS was measured in the background 3 and 7 days and 1, 2 and 3 months after TBI. Tests including open field, elevated plus maze, object location, new object recognition tests (NORT) and Barnes maze with reversal learning were used to assess behavioral changes in acute and late TBI periods. The elevation of CS on day 3 after TBI was accompanied by early CS-dependent objective memory impairments detected in NORT. Blood CS levels > 860 nmol/L predicted delayed mortality with an accuracy of 0.947. Ipsilateral neuronal loss in the hippocampal dentate gyrus, microgliosis in the contralateral dentate gyrus and bilateral thinning of hippocampal cell layers as well as delayed spatial memory deficits in the Barnes maze were revealed 3 months after TBI. Because only animals with moderate but not severe posttraumatic CS elevation survived, we suggest that moderate late posttraumatic morphological and behavioral deficits may be at least partially masked by CS-dependent survivorship bias. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption is characterized by disturbances of neuroplasticity. Brain-derived neurotrophic factor (BDNF) is believed to be critically involved in this process. Here we aimed to review actual experimental and clinical data related to BDNF participation in neuroplasticity in the context of alcohol dependence. As has been shown in experiments with rodents, alcohol consumption is accompanied by the brain region-specific changes of BDNF expression and by structural and behavioral impairments. BDNF reverses aberrant neuroplasticity observed during alcohol intoxication. According to the clinical data parameters associated with BDNF demonstrate close correlation with neuroplastic changes accompanying alcohol dependence. In particular, the rs6265 polymorphism within the BDNF gene is associated with macrostructural changes in the brain, while peripheral BDNF concentration may be associated with anxiety, depression, and cognitive impairment. Thus, BDNF is involved in the mechanisms of alcohol-induced changes of neuroplasticity, and polymorphisms within the BDNF gene and peripheral BDNF concentration may serve as biomarkers, diagnostic or prognostic factors in treatment of alcohol abuse. [ABSTRACT FROM AUTHOR]

Background: Many studies indicate a significant role of GDNF in the pathogenesis of the mood disorders, including bipolar disorder (BD) and major depressive disorder (MDD). Potentially, neurotrophic factors in lacrimal fluid (LF) could become biomarkers of various specific disorders. The aim of this study was to assess GDNF levels in LF and blood serum (BS) of patients with a current depressive episode (cDE).Methods: We studied the glial cell line-derived neurotrophic factor (GDNF) concentration in the LF and BS of 39 healthy controls and 137 patients with a current depressive episode (cDE) (both subgroups members were 20-49 years): BD - 46 patients, MDD - 91 patients.Results: GDNF concentration in BS of women with MDD was significantly lower than in men. In BD patients, univariate linear regression analysis revealed significant correlations between GDNF concentration in the LF and the use of anxiolytics or antidepressants. These correlations were confirmed by the multivariate linear regression analysis. A significant correlation between GDNF concentrations in the LF and BS was found in controls.Limitations: The unequal proportion of men in the BD group did not permit adjusting GDNF concentrations for sex. The collected LF was stimulated, which could influence GDNF levels. It should also be noted that the patients included in the study were not treatment- naïve.Conclusions: Our findings suggest that GDNF concentration in LF could be a biomarker of the cDE (both unipolar and bipolar), though the sensitivity of this potential biomarker may be lower in depressive patients with anxiety symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is believed to play a crucial role in the mechanisms underlying opiate dependence; however, little is known about specific features and mechanisms regulating its expression in the brain under these conditions. The aim of this study was to investigate the effects of acute morphine intoxication and withdrawal from chronic intoxication on expression of BDNF exon I-, II-, IV-, VI- and IX-containing transcripts in the rat frontal cortex and midbrain. We also have studied whether alterations of BDNF exon-specific transcripts are accompanied by changes in association of well-known transcriptional regulators of BDNF gene-phosphorylated (active form) cAMP response element binding protein (pCreb1) and methyl-CpG binding protein 2 (MeCP2) with corresponding regulatory regions of the BDNF gene. Acute morphine intoxication did not affect levels of BDNF exons in brain regions, while spontaneous morphine withdrawal in dependent rats was accompanied by an elevation of the BDNF exon I-containing mRNAs both in the frontal cortex and midbrain. During spontaneous morphine withdrawal, increased associations of pCreb1 were found with promoter of exon I in the frontal cortex and promoters of exon I, IV and VI in the midbrain. The association of MeCP2 with BDNF promoters during spontaneous morphine withdrawal did not change. Thus, BDNF exon-specific transcripts are differentially expressed in brain regions during spontaneous morphine withdrawal in dependent rats and pCreb1 may be at least partially responsible for these alterations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate ciliary neurotrophic factor (CNTF) level in blood serum (BS) and lacrimal fluid (LF) of people with epilepsy (PWE). Methods: A case-control study of 72 consecutive patients with focal epilepsy (cases, epilepsy group) and 60 age- and gender-matched healthy volunteers (controls) was performed. Based on comorbid depression, two subgroups of PWE were formed. CNTF level was measured by an enzyme-linked immunosorbent assay (ELISA) in the BS and LF. For measurements of low CNTF levels in the BS, the methodology previously improved by the authors was applied. Results: As compared to controls, CNTF level (pg/mL) in PWE was increased both in the BS (7.0±2.9 vs. 3.7±2.0, P<0.000) and in LF (34.0±8.0 vs. 30.6±4.8, P=0.005). No significant correlation was found between CNTF level in the BS and LF either in PWE or in controls. No impact of comorbid depression or any demographic or clinical parameters studied on CNTF level in the BS or LF of PWE could be detected. Conclusions: In patients with focal epilepsy, CNTF level is increased both in the BS and LF, though without correlation between them. No association of CNTF levels with age, gender, or clinical parameters, as well as depression occurrence, was found. High CNTF levels in the BS and LF could be considered as non-invasive biomarkers of focal epilepsy. [ABSTRACT FROM AUTHOR]

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). 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. 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. Further studies are needed for better understanding of the pathophysiology of PSE and searching the prevention strategies. • Cumulative risk for PSE is 12-15% after hemorrhagic and 7-9% after ischemic stroke, and increases to 11-16% in middle age. • Hemorrhage, severe stroke, cortical lesion, early seizures occurrence and young age are the most crucial PSE predictors. • Hemosiderin deposition, slow neurological recovery, acute epileptiform abnormalities remain as possible predictors for PSE. • Stroke creates conditions for destabilization of cell membranes, increased excitatory and decreased inhibitory inputs. • Statins might have the capability to attenuate processes contributing to maladaptive plasticity in the penumbra area. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of the study was to explore the involvement of cell cycle events in the neuronal death induced by repeated seizures. Pentylenetetrazole (PTZ) kindling was used as a model of seizure-induced hippocampal neurodegeneration. Immunohistochemical approach was applied to detect cell cycle markers (cyclins and cycline-dependent kinases) in hippocampus. PTZ-kindling in rats induced moderate neuronal cell loss in hippocampal fields CA1, CA 3, CA 4, and dentate gyrus. The majority of damaged cells in hippocampi of PTZ-kindled rats were cycline B1 positive, while no expression of either other cell cycle markers or TUNEL-positive (apoptotic) nuclei could be revealed. Since cycline B1 expression has been described in hippocampal neurons of patients with temporal lobe epilepsy by [Z. Nagy, M.M. Esiri, Neuronal cyclin expression in the hippocampus in temporal lobe epilepsy, Exp. Neurol. 150 (1998) 240–247], it is suggested that PTZ-kindling may be a suitable model to study the mechanisms of seizure-induced neuronal death. [Copyright &y& Elsevier]

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats. [ABSTRACT FROM AUTHOR]

• Acute TBI differentially affects epileptiform activity in male Sprague-Dawley rats. • One week after TBI 7 Hz spike-wave discharges (SWDs) increase in half or rats. • SWDs are accompanied by freezing and anxiety behavior. • Glial activation occurs in ipsilateral neocortex and hippocampal dentate gyrus. • SWD number positively correlates with cortical but not hippocampal damage. Unprovoked seizures in the late period of traumatic brain injury (TBI) occur in almost 20% of humans and experimental animals, psychiatric comorbidities being common in both situations. The aim of the study was to evaluate epileptiform activity in the early period of TBI induced by lateral fluid percussion brain injury in adult male Srague-Dawley rats and to reveal potential behavioral and pathomorphological correlates of early electrophysiological alterations. One week after TBI the group of animals was remarkably heterogeneous regarding the incidence of bifrontal 7-Hz spikes and spike-wave discharges (SWDs). It consisted of 3 typical groups: a) rats with low baseline and high post-craniotomy SWD level; b)with constantly low both baseline and post-craniotomy SWD levels; c) constantly high both baseline and post-craniotomy SWD levels. Rats with augmented SWD occurrence after TBI demonstrated freezing episodes accompanying SWDs as well as increased anxiety-like behavior (difficulty of choosing). The discharges were definitely associated with sleep phases. The incidence of SWDs positively correlated with the area of glial activation in the neocortex but not in the hippocampus.The translational potential of the data is revealing new pathophysiological links between epileptiform activity appearance, direct cortical and distant hippocampal damage and anxiety-like behavior, putative early predictors of late posttraumatic pathology. [ABSTRACT FROM AUTHOR]

Neonatal proinflammatory challenge (NPC) may contribute to the development of psychiatric disorders in adults. A double exposure of neonatal rats to lipopolysaccharide, a component of cellular wall of gram-negative bacteria, on postnatal days 3 and 5 provokes the development of depressive- and anxiety-like behaviors. NPC impairs neuroplasticity and cognition in adult animals, significant modifications of neuroplasticity being evident even in adolescence. We studied effects of NPC on microglia and GABAergic neuronal population of the dorsal hippocampus in juvenile male and female rats using immunofluorescent histochemistry. The expression of glutamic acid decarboxylase-67 (GAD67) and calcium-binding proteins calretinin, calbindin, and parvalbumin were used as quantitative markers of GABAergic interneurons and their specific subpopulations, respectively. NPC induced changes of microglial morphology indicating inflammatory activation mostly expressed in CA3 field; the effect was similar in males and females. The number of GAD67 expressing neurons was similar in the dorsal hippocampus of females and males independently on the NPC. The portion of calbindin-immunoreactive GAD67-positive neurons significantly increased while the portion of calretinin-immunoreactive GAD67-positive neurons significantly decreased in the CA1 field of rats exposed to NPC independently on their sex. NPC did not affect the parvalbumin-positive subpopulation of GABAergic neurons in the hippocampus of rats of either sex. These data suggest that NPC-induced modification of GABAergic neuronal population composition under the proinflammatory conditions is involved in the maintenance of excitation/inhibition homeostatic balance in the hippocampus. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are an important component of adaptive response of an organism to stressogenic stimuli, a typical stress response being accompanied by elevation of GC levels in blood. Anti-inflammatory effects of GCs are widely used in clinical practice, while pro-inflammatory effects of GCs are believed to underlie neurodegeneration. This is particularly critical for the hippocampus, brain region controlling both cognitive function and emotions/affective behavior, and selectively vulnerable to neuroinflammation and neurodegeneration. The hippocampus is believed to be the main target of GCs since it has the highest density of GC receptors potentially underlying high sensitivity of hippocampal cells to severe stress. In this review, we analyzed the results of studies on pro- and anti-inflammatory effects of GCs in the hippocampus in different models of stress and stress-related pathologies. The available data form a sophisticated, though often quite phenomenological, picture of a modulatory role of GCs in hippocampal neuroinflammation. Understanding the dual nature of GC-mediated effects as well as causes and mechanisms of switching can provide us with effective approaches and tools to avert hippocampal neuroinflammatory events and as a result to prevent and treat brain diseases, both neurological and psychiatric. In the framework of a mechanistic view, we propose a new hypothesis describing how the anti-inflammatory effects of GCs may transform into the pro-inflammatory ones. According to it, long-term elevation of GC level or preliminary treatment with GC triggers accumulation of FKBP51 protein that suppresses activity of GC receptors and activates pro-inflammatory cascades, which, finally, leads to enhanced neuroinflammation. [ABSTRACT FROM AUTHOR]

Responses of the hypothalamic-pituitary-adrenal axis (HPAA), immune system and metabolic pathways are involved in adaptation to stress, while alterations in these responses have been implicated in the development of major depressive disorder (MDD). Multiple laboratory indices are known to react in response to the acute stress, however, no valid biomarkers have been reported, which can differentiate stress response in depressed individuals. The aim of this study was to assess changes in a set of laboratory parameters in patients with MDD in response to a moderate mental stress and to find potential markers of altered stress reactivity associated with depression. A group of 33 MDD patients and 43 control subjects underwent clinical evaluation to assess depression and anxiety symptoms, as well as heart rate variability (HRV) analysis. Participants were asked to perform a time constrained cognitive task, and selected hormones (cortisol, ACTH), cytokines (IL-6, IL-1β, TNF-α), neurotrophic factors (BDNF, CNTF) and metabolic parameters (glucose, cholesterol, triglycerides) were measured before and 60 min after the task performance. HRV analysis showed increased sympathetic input in MDD patients. The MDD group manifested an elevated HPAA activity as well as IL-6 and CNTF levels at baseline. A specific stress-induced increase in glucose and TNF-α was revealed in the MDD group, which was absent in control subjects. The data confirm the impairments of stress response in MDD and suggest that the reaction of simple metabolic and pro-inflammatory indices to a mild stressogenic challenge may be indicative of a depressive state. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To study brain-derived neurotrophic factor (BDNF) content in aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG). Methods: BDNF was studied in 57 patients with age-related cataract, 55 patients with POAG combined with cataract, and 29 healthy controls (one eye in each person). AH was sampled during cataract surgery. Results: The levels of BDNF in LF and BS did not differ in cataract patients and controls. The concentration of BDNF (pg/mL) in patients with POAG and cataract was lower than in cataract patients in AH (35.2 ± 14.2 vs. 54.6 ± 29.6, P < 0.001), LF (78.0 ± 25.1 vs. 116.2 ± 43.1, P < 0.001), and BS (19230 ± 5960 vs. 22440 ± 7580, P < 0.02), while the AH/LF ratio was similar (0.46 ± 0.18 vs. 0.48 ± 0.19). The AH level of BDNF declined in early POAG and relatively increased in the next stages of the disease, inversely correlating with visual field index (Pearson's correlation coefficient r = -0.404, P = 0.002) and average retinal nerve fiber layer thickness (r = -0.322, P = 0.018). BDNF contents in LF and BS were also the lowest in early POAG. BDNF in AH strongly correlated with its content in LF (r = 0.66, P < 0.000). A formula was suggested to calculate the AH concentration of BDNF basing on its content in LF. Conclusions: BDNF contents are decreased in AH, LF, and BS of patients with POAG demonstrating a significant decrease in the early POAG and relative increase in the next stages of the disease. A strong correlation exists between BDNF contents in AH and LF. [ABSTRACT FROM AUTHOR]

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™ (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. [ABSTRACT FROM AUTHOR]

Wnt signaling is involved in hippocampal development and synaptogenesis. Numerous recent studies have been focused on the role of Wnt ligands in the regulation of synaptic plasticity. Inhibitors and activators of canonical Wnt signaling were demonstrated to decrease or increase, respectively, in vitro long-term potentiation (LTP) maintenance in hippocampal slices (Chen et al. in J Biol Chem 281:11910-11916, 2006; Vargas et al. in J Neurosci 34:2191-2202, 2014, Vargas et al. in Exp Neurol 264:14-25, 2015). Using lentiviral approach to down- and up-regulate the canonical Wnt signaling, we explored whether Wnt/β-catenin signaling is critical for the in vivo LTP. Chronic suppression of Wnt signaling induced an impairment of in vivo LTP expression 14 days after lentiviral suspension injection, while overexpression of Wnt3 was associated with a transient enhancement of in vivo LTP magnitude. Both effects were related to the early phase LTP and did not affect LTP maintenance. A loss-of-function study demonstrated decreased initial paired pulse facilitation ratio, β-catenin, and phGSK-3β levels. A gain-of-function study revealed not only an increase in PSD-95, β-catenin, and Cyclin D1 protein levels, but also a reduced phGSK-3β level and enhanced GSK-3β kinase activity. These results suggest a presynaptic dysfunction predominantly underlying LTP impairment while postsynaptic modifications are primarily involved in transient LTP amplification. This study is the first demonstration of the involvement of Wnt/β-catenin signaling in synaptic plasticity regulation in an in vivo LTP model. [ABSTRACT FROM AUTHOR]

Hair cortisol is regarded as a promising marker of hypothalamic-pituitary-adrenal axis (HPAA) activity alterations due to stress, somatic and mental health conditions. Hair cortisol was previously reported to be elevated in patients with depression, however the data related to remission and recurrent depressive episodes are different. In this study, levels of hair cortisol were assessed in female patients with major depressive disorder (MDD) and the validity of hair cortisol as a marker of HPAA activity in this condition was evaluated. Hair cortisol was measured in 1 cm hair segments of 21 female patients with MDD and 22 female age-matched controls using enzyme-immunoassay analysis. Concurrently, serum cortisol was assessed and psychological status was evaluated using 17-item Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory (BDI) and the Spielberger state trait anxiety inventory (STAI). The levels of hair cortisol were significantly lower in the MDD group, while serum cortisol levels were significantly higher in patients, as compared with controls. A significant negative correlation was found between HAMD-17 scores and hair cortisol. Decreased hair cortisol found in female patients with MDD as compared to controls suggests downregulation of HPAA activity during the preceding month. Further studies are needed to investigate the profiles of hair cortisol at different stages of depressive disorder to establish this parameter as a handy clinical tool. [ABSTRACT FROM AUTHOR]

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-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation related to impairments of local glucocorticoid metabolism and signaling. We have evaluated inflammatory responses induced by acute or chronic combined stress in the cerebral cortex and hippocampus as well as circulating and brain corticosterone (CS) levels as well as expression of corticosterone target genes. The hippocampus showed higher stress-induced expression of the proinflammatory cytokine IL-1β as compared to the cerebral cortex. A month after the termination of the chronic stress, IL-1β mRNA in the cerebral cortex reached control level, while in the hippocampus it remained significantly increased. Under chronic stress, the maladaptive inflammatory response in hippocampus was accompanied by a significant increase in local CS levels, as compared to cerebral cortex. Under acute stress, the increased CS level induced changes in CS-regulated genes expression ( CRF and IGF1), while this phenomenon was not observed after chronic stress. Thus, the hippocampus appears to be more vulnerable to stress-induced inflammation as compared to the neocortex and demonstrates persistent inflammatory response induced by chronic stress. Stress-induced maladaptive inflammatory response is associated with a selective increase in hippocampal CS accumulation and changes in CS signaling. [ABSTRACT FROM AUTHOR]

Olfactory bulbectomy (OBX) in rodents induces a wide spectrum of functional disturbances, including behavioral, neurochemical, and neuromorphological alterations. We have examined the effects of OBX on behavior and the parameters of the cholinergic system in female rats and mice. In rats, OBX resulted in the appearance of some depressive-like behavioral marks, such as the decreased sucrose consumption, hyperactivity, impaired short-term memory and anxiety-like behavioral features, such as shortened presence in the center of the open field arena or open arms of the elevated plus-maze and an enhancement of avoidance behavior. These behavioral abnormalities could be associated with disturbances in hippocampal function, this suggestion being supported by the presence of cellular changes in this brain structure. No effect of OBX on the number of cholinergic neurons in the medial septum-diagonal band as well as on the acetylcholine content and acetylcholinesterase activity in the septum, hippocampus, and neocortex could be detected. In contrast, in mice, OBX impaired spontaneous alternation behavior and decreased the number of cholinergic neurons in the medial septum-diagonal band. These data demonstrate that rats and mice differently respond to OBX, in particular, OBX does not significantly affect the cholinergic system in rats. [ABSTRACT FROM AUTHOR]

We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50 nM beta-amyloid (25–35) 1 h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment. [ABSTRACT FROM AUTHOR]

• 7,8-DHF does not modify drinking in IA2BC paradigm. • 7,8-DHF has weak effect on anxiety-like behavior during early abstinence after IA2BC. • 7,8-DHF enhances SHH in a region-specific manner during early abstinence. A mimetic of brain-derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (7,8-DHF), alleviates some aspects of alcohol abstinence after voluntary alcohol intake in rodents. The interaction between BDNF and sonic hedgehog (SHH) was demonstrated in adult brain in some situations, though relationship between BDNF and SHH during alcohol abstinence remains obscure. We aimed to study effect of 7,8-DHF on drinking pattern, anxiety-like behavior and expression of SHH and a downstream transcription factor, GLI, in the limbic brain structures during early abstinence after voluntary ethanol intake. Male Wistar rats were subjected to intermittent access to 20% ethanol in a two-bottle choice procedure (IA2BC). The animals experienced twenty 24-h sessions of free access to two-bottle choice (water or 20% ethanol) with 24-h withdrawal periods (water only); 7,8-DHF (5 mg/kg, i.p.) was administered one hour prior to each alcohol access session. Anxiety-like behavior was estimated in the open-field (OFT) and elevated plus-maze (EPM) tests on the first and second days of abstinence, respectively. The expression of SHH and GLI was analyzed on the third day after withdrawal in the frontal cortex, hippocampus and striatum. Repeated measures ANOVA did not show significant main effect of 7,8-DHF injections during IA2BC on ethanol intake and ethanol preference over water. As expected, pair-wise comparisons of OFT and EPM data by Mann-Whitney U test revealed elevated anxiety-like behavior during early abstinence in IA2BC paradigm as compared with control group. When all groups were included in the analysis, Kruskal-Wallis ANOVA did not show significant differences in time spent in the center zone of the OFT and number of entries. However, time spent in the open arms of the EPM but not number of entries differed significantly between the groups studied according to Kruskal-Wallis ANOVA. Factorial ANOVA followed by Tukey's HSD post hoc test demonstrated significant elevation of SHH protein levels in the hippocampus and striatum but not in the frontal cortex of animals with access to ethanol and administered with 7,8-DHF as compared with respective animals without 7,8-DHF. GLI expression changed only in the hippocampus; its protein level increased in control animals administered 7,8-DHF. Thus, 7,8-DHF administration during IA2BC procedure induces region-specific levels elevation of SHH in the brain, but does not significantly change drinking pattern and anxiety-like behavior during early abstinence. [ABSTRACT FROM AUTHOR]

Highlights: [•] Aβ(25–35) induces transient impairment in contextual fear conditioning. [•] Aβ(25–35) induces progressive decrease of ChAT expressing neurons in MS. [•] Aβ(25–35) induces long-term decline in ChAT and VaChT mRNA in MS. [•] Aβ(25–35) induces loss of septal neurons cholinergic phenotype without cell death. [ABSTRACT FROM AUTHOR]

Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stressinduced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease-a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states. [ABSTRACT FROM AUTHOR]

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed critical differences between them along with similarities (Smith et al. 2015; Morris et al. 2016). In this study, a direct comparison of MCAO-KM and MCAO-LM in rats was performed. Three days after MCAO, infarct volume, mortality rate, neurological deficit, and weight loss were similar in these models. MCAO-LM rats showed an increase in ACTH levels, while MCAO-KM rats demonstrated elevated corticosterone and interleukin-1β in blood serum. Corticosterone accumulation was detected in the frontal cortex (FC) and the hippocampus of the MCAO-KM group. IL1β beta increased in the ipsilateral hippocampus in the MCAO-KM group and decreased in the contralateral FC of MCAO-LM rats. Differences revealed between MCAO-KM and MCAO-LM suggest that corticosterone and interleukin-1β release as well as hippocampal accumulation is more expressed in MCAO-KM rats, predisposing them to corticosterone-dependent distant neuroinflammatory hippocampal damage. The differences between two models, particularly, malfunction of the hypothalamic–pituitary–adrenal axis, should be considered in the interpretation, comparison, and translation of pre-clinical experimental results. [ABSTRACT FROM AUTHOR]

• In patients with focal epilepsy, BDNF level is decreased both in blood serum and lacrimal fluid. • No association of BDNF levels with age and epilepsy characteristics, as well as the occurrence of depression, was found. • Low BDNF level in lacrimal fluid could be considered as a non-invasive biomarker of focal epilepsy. To evaluate brain-derived neurotrophic factor (BDNF) level in blood serum (BS) and lacrimal fluid (LF) of people with epilepsy (PWE). It was a case-control study of 72 consecutive patients with focal epilepsy (cases, Epilepsy group) and 60 age- and gender-matched healthy volunteers (controls). Based on comorbid depression, two subgroups of PWE were formed. BDNF level was measured by enzyme-linked immunosorbent assay (ELISA) in BS and LF. Compared to controls, BDNF level (pg/mL) in PWE was lower both in BS (22,520 ± 3810 vs. 26,360 ± 3090, P < 0.000) and in LF (100.8 ± 23.3 vs. 113.4 ± 19.3, P = 0.001). However, no significant correlation was found between BDNF level in BS and LF either in the Epilepsy group or in controls. No impact of comorbid depression on BDNF level was found either in BS or LF of PWE. We revealed a higher BDNF level in LF of men as compared to women in controls and a similar non-significant trend in PWE. Higher BDNF level in BS of PWE receiving valproates versus other AEDs was found, however, a relatively small number of observations and use of polytherapy in most cases should be taken into account. In patients with focal epilepsy, BDNF level is decreased both in BS and LF, though with no correlation between them. No association of BDNF levels with age and epilepsy characteristics, as well as the occurrence of depression, was found. Low BDNF level in LF could be considered as a non-invasive biomarker of focal epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: According to different studies, between 5% and 10% of people suffer a single isolated seizure episode at some time in their life. However, little is known about the effects of a single seizure episode on cognitive function, and clinical investigations of this issue are not easy to perform. In this situation, animal models may be a reasonable choice. The aim of our study was to follow the time course of delayed effects of generalized clonic-tonic convulsions on learning and memory functions in rats. A clonic-tonic seizure episode was induced by a single i.p. injection of pentylenetetrazole (70mg/kg). Different behavioral tests were performed between days 10 and 100 after the convulsant administration. A single seizure episode resulted in a gradual decline in short-term memory function as assessed by novel object recognition and social recognition tests. The seizure episode induced a quick increase in hippocampal cell proliferation; however, the excessive newly generated cells seemed to be eliminated by the time of obvious cognitive impairment. These observations are indicative of a slowly developing and long-lasting influence of a single seizure episode on cognitive function. A rather long time period between the seizure episode and the manifestations of cognitive decline provides a window for a possible therapeutic intervention, and an elaboration of such “post-conditioning” treatments may be a promising opportunity to prevent subsequent mental impairments in patients. [Copyright &y& Elsevier]

Effects of a chronic combined unpredictable stress on activities of two cell death-related proteases, calpain and cathepsin B, were studied along with indices of nitrergic system in rat brain structures. Male Wistar rats were subjected to a 2-week-long combined stress (combination of unpaired flash light and moderate footshock associated with a white noise session). Stress resulted in a significant loss in the body and thymus weight and increased defecation in the open field test, though neither motor and exploratory activity, nor plasma corticosterone differed from the respective control levels. Decreased calpain activity and increased cathepsin B activity were demonstrated in the hippocampus of stressed rats (previously we have shown that caspase-3 activity was significantly suppressed in the brain of rats subjected to same type of stress). A significant reduction in the number of NOS-containing neurons was accompanied by a chronic stressinduced decline in NOS activity in the neocortex. Similar changes were observed in the hippocampus. However, levels of NO metabolites were elevated in both structures. Thus, stress-induced structural modifications in the brain may be mediated by disturbances in the nitrergic system and increased lysosomal proteolysis. [ABSTRACT FROM AUTHOR]