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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]

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]

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]

• 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]

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]

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]

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]

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

Abstract: Effects of concurrent intracerebroventricular administration of amyloid-β peptide 25–35 (Aβ(25–35)) and the proinflammatory cytokine tumor necrosis factor-α (TNFα) to rats were investigated. A battery of behavioral tests including radial arm maze, passive avoidance, elevated plus-maze and forced swim test as well as histological methods were used. A single administration of Aβ(25–35) induced delayed behavioral deficits manifested in reference and working memory disturbances in the radial maze task involving spatial memory. However, no effects of Aβ(25–35) on learning or retention in a passive avoidance test could be revealed. Aβ(25–35) appeared to decrease anxiety without affecting depression-like behavior in the rats. Aβ(25–35)-induced cognitive deficits could be related to the moderate neuronal cell loss found in the hippocampal CA1 field. Though administration of TNFα did not impair learning and memory of rats in the radial maze, it induced gross changes in their behavior during passive avoidance training. Though TNFα did not protect against Aβ(25–35)-induced neuronal cell loss in the CA1 field of hippocampus, co-administration of TNFα with Aβ(25–35) resulted in an improvement of reference memory impaired by the amyloid peptide, but not of working memory. [Copyright &y& Elsevier]

Abstract: A large body of evidence implicates β-amyloid peptide (βAP) and other derivatives of the evolutionarily highly conserved amyloid precursor protein (APP) in the pathogenesis of Alzheimer''s disease. However, the functional relationship of APP and its proteolytic derivatives to synaptic plasticity is not well known. We demonstrate that 30min exposure to the 25–35 fragment of βAP do not markedly change the dynamics of synaptic responses in identified neurons of terrestrial snail while a significant decrease of long-term sensitization was observed after 180min βAP bath application. In the behavioral experiments, a significant reduction of sensitization, and decreased ability to develop food-aversion conditioning was observed after βAP injection. Our results clearly demonstrate that the neurotoxic 25–35 fragment of βAP may play a significant role in behavioral plasticity by chronically eliminating certain underlying forms of synaptic plasticity. The study also proposes a novel invertebrate model to Alzheimer''s disease. [Copyright &y& Elsevier]

Amyloid β-peptide (Aβ) plays an important role in the pathophysiology of Alzheimer''s disease. The relationship between amnesia induced by central administration of aggregated Aβ(25–35) and neurodegeneration in the hippocampus was investigated. One month after a single intracerebroventricular injection of Aβ(25–35) (15 nmol), male Wistar rats were tested in an eight-arm radial maze. A quantitative evaluation of cell number in hippocampal regions was carried out on H&E-stained brain sections of rats used in the behavioral study. Indices of free radical-mediated processes in the hippocampus were evaluated in additional groups of animals 1, 3, 5, and 30 days after surgery. Aβ(25–35) induced impairments of working and reference memory (RM) as well as neurodegeneration in the CA1 but not in the CA3 field of the hippocampus. A significant correlation between both reference and working memory (WM) impairments and the neuronal cell loss in the hippocampal CA1 region was demonstrated. A gradually developing oxidative stress was evident in the hippocampus of rats treated with Aβ(25–35) as indicated by the increase in 2-thiobarbituric acid (TBARS) reactive substances and superoxide generation. These data suggest the involvement of oxidative stress in Aβ(25–35)-induced neurodegeneration and a relation between memory impairment and neurodegeneration in the CA1 subfield of the hippocampus. [Copyright &y& Elsevier]

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

To enhance the lipophilicity of the NO-synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine, its bridgehead analogue was suggested on the basis of molecular modeling; the synthetic routes to new 3-thia-1-azabicyclo[3.3.1]nonane derivatives and the results of their biological testing are presented. [ABSTRACT FROM AUTHOR]

2-Thia-4-azabicyclo[3.3.1]non-3-en-3-amine was synthesized as a lipophilic analogue of NO-synthase inhibitor 2-amino-5,6-dihydro- 4H-1,3-thiazine and found to be a potent inhibitor of inducible NO-synthase in vitro. The crystal structure of the key intermediate 2-thia-4-azabicyclo[3.3.1]nonane-3-thione (obtained by cyclization of trans-3-bromocyclohexylamine with carbon disulfide) was determined by X-ray analysis. [Copyright &y& Elsevier]