Oleuropein Has Modulatory Effects on Systemic Lipopolysaccharide-Induced Neuroinflammation in Male Rats.

BACKGROUND: Neuroinflammation induced by systemic inflammation is a risk factor for developing chronic neurologic disorders. Oleuropein (OLE) has antioxidant and anti-inflammatory properties; however, its effect on systemic inflammation-related neuroinflammation is unknown. OBJECTIVES: This study aimed to determine whether OLE protects against systemic lipopolysaccharide (LPS)-induced neuroinflammation in rats. METHODS: Six-wk-old Wistar rats were randomly assigned to 1 of the following 5 groups: 1) control, 2) OLE-only, 3) LPS + vehicle, 4) OLE+LPS (O-LPS), and 5) a single-dose OLE + LPS (SO-LPS group). OLE 200 mg/kg or saline as a vehicle was administered via gavage for 7 d. On the seventh day, 2.5 mg/kg LPS was intraperitoneally administered. The rats were decapitated after 24 h of LPS treatment, and serum collection and tissue dissection were performed. The study assessed astrocyte and microglial activation using glial fibrillary acidic protein (GFAP) and CD11b immunohistochemistry, nod-like receptor protein-3, interleukin (IL)-1ß, IL-17A, and IL-4 concentrations in prefrontal and hippocampal tissues via enzyme-linked immunosorbent assay, and total antioxidant/oxidant status (TAS/TOS) in serum and tissues via spectrophotometry. RESULTS: In both the O-LPS and SO-LPS groups, LPS-related activation of microglia and astrocytes was suppressed in the cortex and hippocampus (P < 0.001), excluding cortical astrocyte activation, which was suppressed only in the SO-LPS group (P < 0.001). Hippocampal GFAP immunoreactivity and IL-17A concentrations in the dentate gyrus were higher in the OLE group than those in the control group, but LPS-related increases in these concentrations were suppressed in the O-LPS group. The O-LPS group had higher cortical TAS and IL-4 concentrations. CONCLUSIONS: OLE suppressed LPS-related astrocyte and microglial activation in the hippocampus and cortex. The OLE-induced increase in cortical IL-4 concentrations indicates the induction of an anti-inflammatory phenotype of microglia. OLE may also modulate astrocyte and IL-17A functions, which could explain its opposing effects on hippocampal GFAP immunoreactivity and IL-17A concentrations when administered with or without LPS.

Peripheral nesfatin-1 reduces basal brain activity but has limited effect on epilepsy-like conditions.

In this study, we investigated the effects of peripheral nesfatin-1 on basal brain activity and 4-aminopyridine (4-AP)-induced epileptiform activity, and its relationship with the electrocorticogram (ECoG) power spectrum and EEG bands. Forty-nine male Wistar rats were divided into seven groups: control sham, 4-AP (2.5 mg/kg i.p.), Nesfatin-1 (1, 2, and 4 µg/kg i.p.), Nesfatin-1 (2 µg/kg) post-treatment, and Nesfatin-1 (2 µg/kg) pre-treatment. Recordings were conducted for 70 min under ketamine/xylazine (90/10 mg/kg) anesthesia. In the post-treatment group, nesfatin-1 was injected 20 min after 4-AP induction. In the pre-treatment groups, nesfatin-1 was administered following basal recordings and before 4-AP injection. 4-AP induced epileptiform activity in all animals, peaking at 30 min. Nesfatin-1 (2 µg/kg) reduced basal brain activity (p < 0.05) and decreased alpha, delta, and theta bands in ECoG. Post-treatment of nesfatin-1 did not affect 4-AP-induced activity (p > 0.05) but increased gamma band activity (p > 0.05). Pre-treatment of nesfatin-1 reduced epileptiform activity between 50 and 60 min (p < 0.05), decreased delta bands, and increased gamma bands (p > 0.05). We conclude that peripheral nesfatin-1 modulates normal brain activity but has limited effects on abnormal discharges.

How does l-theanine treatment affect the levels of serum and hippocampal BDNF, insulin and adipocytokines in diabetic rats?

BACKGROUND: Diabetes Mellitus (DM), a metabolic disease characterized by the increased blood glucose level, insulin deficiency or ineffectiveness, may cause structural and functional disorders in the brain. l-Theanine (LTN) has the relaxing, psychoactive, antidepressant, anti-inflammatory and antinecrotic properties, and regulates the functions of hippocampus (HP) in brain. In the present study, the aim was to identify the effects LTN on the levels of BDNF, insulin and adipocytokines (TNF-α, leptin, adiponectin and resistin) in both HP and serum of diabetic rats. METHODS: 32 male Wistar rats were divided into four groups (n = 8/group): Control, LTN, DM and DM + LTN. Diabetes was induced by by nicotinamide/streptozotocin. 200 mg/kg/day LTN treatment was applied for 28 days. The serum and hippocampal levels of the parameters were determined by using commercial ELISA kits. Additionally, HP tissues examined histopathologically. RESULTS: LTN treatment significantly decreased leptin and adiponectin levels in HP tissues in diabetic rats (p < 0.05). Although it decreased the insulin level in both serum and HP, this was not statistically significant. No significant effect on other parameters was observed (p > 0.05). In histopathological analysis, although the damage was reduced by LTN in all sections of HP, this change was significant mainly in CA3 region (p < 0.05). CONCLUSION: It was concluded that LTN has the ability to reduce hippocampal degeneration and modulates adipocytokines in diabetic rats.

Fisetin decreases the duration of ictal-like discharges in mouse hippocampal slices.

There is an increasing interest in the biological and therapeutic effects of fisetin, a natural phenolic compound. Fisetin has affinity on some neuronal targets and may have the potential to modulate neuronal activity. In this study the effects of acute application of fisetin on synchronized events were evaluated electro-physiologically. Besides, interaction of fisetin with closely related channels were investigated in silico. Acute horizontal hippocampal slices were obtained from 32- to 36-day-old C57BL/6 mice. Extracellular field potentials were recorded from CA3 region of the hippocampus. Bath application of 4 aminopyridine (4AP, 100 µM) initiated ictal- and interictal-like synchronized epileptiform discharges in the brain slices. Fifty micromolar fisetin was applied to the recording chamber during the epileptiform activity. The duration and frequencies of both ictal-like and interictal-like activities were calculated from the electrophysiological records. Molecular docking was performed to reveal interaction of fisetin on GABA-A, NMDA, AMPA receptors, and HCN2 channel, which are neuronal structures directly involved in recorded activity. Although fisetin does not affect basal neuronal activity in brain slice, it reduced the duration of ictal-like discharges significantly. Molecular docking results indicated that fisetin has no effect on GABA-A, NMDA, and AMPA receptors. However, fisetin binds to the (5JON) HCN2 channel strongly with the binding energy of -7.66 kcal/mol. Reduction on the duration of 4AP-induced ictal-like discharges can be explained as HCN channels can cause an inhibitory effect via enhancing M-type K + channels which increase K outward currents.

Phoenixin-14 reduces the frequency of interictal-like events in mice brain slices.

Phoenixin-14 (PNX-14) has a wide bioactivity in the central nervous system. Its role in the hypothalamus has been investigated, and it has been reported that it is involved in the regulation of excitability in hypothalamic neurons. However, its role in the regulation of excitability in entorhinal cortex and the hippocampus is unknown. In this study, we investigated whether i. PNX-14 induces any synchronous discharges or epileptiform activity and ii. PNX-14 has any effect on already initiated epileptiform discharges. We used 350 µm thick acute horizontal hippocampal-entorhinal cortex slices obtained from 30- to 35-day-old mice. Extracellular field potential recordings were evaluated in the entorhinal cortex and hippocampus CA1 region. Bath application of PNX-14 did not initiate any epileptiform activity or abnormal discharges. 4-Aminopyridine was applied to induce epileptiform activity in the slices. We found that 200 nM PNX-14 reduced the frequency of interictal-like events in both the entorhinal cortex and hippocampus CA1 region which was induced by 4-aminopyridine. Furthermore, PNX-14 led to a similar suppression in the total power of local field potentials of 1-120 Hz. The frequency or the duration of the ictal events was not affected. These results exhibited for the first time that PNX-14 has a modulatory effect on synchronized neuronal discharges which should be considered in future therapeutic approaches.

Effect of a high sucrose and high fat diet in BDNF (+/-) mice on oxidative stress markers in adipose tissues.

The purpose of this study was to investigate the effects of a high fat and a high sucrosediet in wild type and BDNF (+/-) mice on oxidative stress in epididymal and subcutaneousadipose tissues by measuring different markers of oxidative stress and antioxidant enzymes. Wild type (WT) and BDNF (+/-) male mice were divided into six groups receiving fed control diet (CD), high sucrose diet (HSD), or high fat diet (HFD) for four months. Levels of 3-nitrotyrosine (3-NT) increased in the HFD-fed BDNF (+/-) mice, while 4-hydroxynonenal (4-HNE) levels increased in the CD and HFD-fed BDNF (+/-) groups. Malondialdehyde (MDA) levels decreased in subcutaneous tissue compared to epididymal adipose tissue, independently of diet type. Superoxide dismutase (SOD) activity was reduced by HFD (p < 0.05), butglutathione peroxidase (GSH-Px) activity was increased by HSD in epididymal adipose tissuein BDNF (+/-) mice (p < 0.05). GSH-Px activities was increased by CD and HFD in subcutaneous adipose tissue of BDNF (+/-) (p < 0.05). SOD2 and GSH-Px3 expressions were only decreased by HSD in epididymal and subcutaneous adipose tissues of BDNF (+/-) mice (p < 0.05). In conclusion, reduced BDNF may increase OS in epididymal adipose tissue, but not in subcutaneous adipose tissue following HSD and HFD.

Effects of housing conditions on stress, depressive like behavior and sensory-motor performances of C57BL/6 mice.

BACKGROUND: The effects of housing conditions on animal physiology, behavior or stress are still debated. The aim of this study was to investigate the effects of three different housing systems, individually ventilated cages (IVC), classical small cages with floor surface area of 500 cm2 (CC500) and classical large cages with floor surface area of 800 cm2 (CC800) on body weight, sensory-motor performances, depression-like behavior, plasma corticosterone and brain oxidative stress parameters in C57BL/6 mice. The mice housed in one of the cages from birth to 6 months of age. Hang wire and adhesive removal tests were performed to evaluate somatosensory and motor performances. The extent of depression was determined by the forced swim test. Blood corticosterone levels were measured. In addition, brain malondialdehyde (MDA), total antioxidant status (TAS) and total oxidant status (TOS) levels were analyzed. RESULTS: The depression-like behavior of the groups was similar. Although there were no significant differences in hang wire test among groups, CC500 group required longer durations in adhesive removal test. The body weight and plasma corticosterone levels of CC800 group were significantly higher than other groups. The oxidative stress parameters were highest in CC500 cage. CONCLUSIONS: Our study showed that the least stressful housing condition was IVC cage systems. Interestingly, the number of mice in the classical cages had a significant effect on stress levels and sensory-motor performance.

Alarin potentiates ongoing epileptiform activity in rat brain slices: an in vitro electrophysiological study.

Alarin is a newly discovered neuropeptide that belongs to the galanin peptide family with a wide range of bioactivity in the nervous system. Its function in the brain's autonomic areas has been studied, and it has been reported that alarin is involved in the regulation of excitability in hypothalamic neurons. Its role in the regulation of excitability in the hippocampus, however, is unknown. In this study, we investigated if alarin induced any synchronous discharges or epileptiform activity, and if it had any effect on already initiated epileptiform discharges. We used thick acute horizontal hippocampal slices obtained from 30­ to 35­day­old rats. Extracellular field potential recordings were evaluated in the CA1 region of the hippocampus. Our data demonstrated that, alarin application did not result in any epileptiform activity or abnormal discharges. 4­aminopyridine was applied to induce epileptiform activity in the slices. We found that alarin increased the frequency of interictal­like events and the mean power of local field potentials in the CA1 region of the hippocampus, which was induced by 4­aminopyridine. These results demonstrated for the first time that alarin has a modulatory effect on synchronized neuronal discharges and showed the contribution of the neuropeptide alarin to epilepsy­like conditions.

Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study.

In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin-treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 µl). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability.

Sensory­motor performance and neurochemical effects in the cerebral cortex of brain­derived neurotrophic factor heterozygous mice fed a high­cholesterol diet.

Reports suggest that a high­cholesterol diet may induce neuroinflammation, oxidative stress, and neurodegeneration in brain tissue. Brain­derived neurotrophic factor (BDNF) might play a role in protecting against changes induced by high cholesterol. We aimed to assess behavioral correlates and biochemical alterations in the motor and sensory cortices following a high­cholesterol diet under normal and reduced BDNF concentrations. C57Bl/6 strain, wild­type (WT) and BDNF heterozygous (+/­) mice were used to reveal the effects of endogenous BDNF concentrations. We compared diet and genotype effects using four experimental groups: WT and BDNF heterozygous (+/­) groups of mice were each fed a normal or high­cholesterol diet for 16 weeks. The cylinder test and wire hanging test were performed to evaluate neuromuscular deficits and cortical sensory­motor functions, respectively. In addition, neuroinflammation was assessed by tumor necrosis factor alpha and interleukin 6 levels measured in the somatosensory and motor areas. Additionally, MDA levels and SOD and CAT activity were evaluated as oxidative stress parameters. Results showed that a high­cholesterol diet significantly impaired behavioral performance in the BDNF (+/­) group. Diet did not change the levels of neuroinflammatory markers in any of the groups. However, MDA levels, an indicator of lipid peroxidation, were significantly higher in the high­cholesterol­fed BDNF (+/­) mice. The results suggest that BDNF levels might be a critical factor in determining the extent of neuronal damage induced in the neocortex by a high­cholesterol diet.

The regulation of adipokines related to obesity and diabetes is sensitive to BDNF levels and adipose tissue location.

PURPOSE: The role of BDNF in adipose tissue metabolism is poorly understood. We investigated the effects of decreased levels of BDNF on the expression of major adipokines in different fat depots (e.g., subcutaneous and epididymal) of mouse groups fed three different diet protocols. METHODS: BDNF heterozygous (+ / -) mice were used to evaluate the effect of reduced BDNF levels. Six groups of C57BL/6 J breed wild type (WT) and BDNF (+ / -) mice were formed. These groups were fed, respectively, a control diet (CD), a high-fat diet (HFD), and a high-sucrose diet (HSD) for 4 months. Serum samples and adipose tissues were used for biochemical assays. The serum concentrations and tissue expression levels of leptin, adiponectin, and resistin were measured. RESULTS: Compared to the CD-fed WT group (control group), serum leptin and leptin expression levels were found to be higher in all experimental groups. Serum adiponectin levels were lower in the BDNF (+ / -) groups and HFD-fed WT group than in the control group. Epididymal adiponectin expression was found to be lower in the HFD-fed BDNF (+ / -) group and higher in HSD-fed groups than in the control group. Compared to the control group, adiponectin expression increased in the WT groups in subcutaneous adipose tissue. Serum resistin levels were elevated in the HFD-fed groups. Resistin expression in epididymal adipose tissue was lower in the CD-fed and HFD-fed groups than in the control group. CONCLUSIONS: BDNF levels and diet differentially affect the expression of adipokines in different fat tissues in the body. BDNF may play a protective role in obesity and diabetes.

7,8-Dihydroxyflavone alleviates Endoplasmic Reticulum Stress in cafeteria diet-induced metabolic syndrome.

AIMS: Prolonged Endoplasmic Reticulum Stress (ERS) is involved in the pathogenesis of metabolic syndrome, including type-2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. There have been significant efforts to discover molecules to treat ERS and/or to ameliorate associate symptoms. In this study, we investigated the effect of 7,8-Dihydroxyflavone (7,8-DHF) on ERS in liver and pancreas tissues in a cafeteria (CAF) diet induced metabolic syndrome model. MAIN METHODS: Male C57BL/6 mice were fed CAF diet for 16 weeks and 7,8-DHF was administered intraperitoneally (5 mg/kg/day) for last four weeks. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in liver and pancreas tissues, insulin and interleukin-1ß (IL-1ß) in serum were analyzed by ELISA method and serum biochemistry parameters were analyzed with autoanalyzer. GRP78 and CHOP gene expression levels were determined by qRT-PCR. In addition, histopathological analyzes were performed on liver and pancreas tissues. KEY FINDINGS: Findings revealed that CAF diet caused metabolic abnormalities, insulin resistance and inflammation in serum and triggered ERS in pancreas and liver tissues. 7,8-DHF treatment significantly reduced metabolic abnormalities by reducing serum biochemical parameters, HOMO-IR and IL-1ß levels. qRT-PCR and ELISA results indicated that 7,8-DHF treatment down-regulated GRP78 and CHOP expression and protein levels in the liver and GRP78 expression in pancreas. Efficiency of 7,8-DHF in these tissues was also demonstrated by histopathological tests. SIGNIFICANCE: In conclusion, CAF diet-induced metabolic syndrome model, 7,8-DHF suppressed ERS and ERS-induced metabolic disorders in both liver and pancreas. Therefore, 7,8-DHF may potentially be a novel therapeutic compound to ameliorate ERS and related metabolic symptoms.

7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices.

In the central nervous system, Tropomyosin-receptor-kinase B (TrkB) signaling is involved in neuronal survival, differentiation as well as in regulation of synaptic transmission and excitability. As its powerful potential to modulate neuronal functions, TrkB pathway is an attractive target for novel drugs and treatment of common neurological disorders. 7,8-Dihydroxyflavone (DHF), a TrkB receptor agonist, has similar properties with neurotrophin Brain Derived Neurotropic Factor (BDNF). DHF is reported to have a number of beneficial effects in neuroprotection, against depression and improving learning and memory. However, the outcome of acute application of DHF on the excitability of neuronal circuits is not clear. Especially the effects of DHF on synchronized epileptiform activity are not known. In this study, we investigated whether DHF induces epileptiform activity in brain slices and DHF has any effect on already initiated epileptiform discharges. We used acute horizontal hippocampal-entorhinal cortex slices obtained from 30 to 35 days of mice. Extracellular field potential recordings were obtained from entorhinal cortex (EC) and hippocampus CA1 region. DHF did not initiate any epileptiform activity or abnormal discharges. However, DHF increased the frequency of 4 aminopyridine (4AP) induced ictal and interictal events in both EC and CA1. The duration of induced ictal charges were also prolonged upon DHF application. In a number of slices, both EC and CA1, DHF led to ictogenesis. These results suggest that the acute activation of TrkB by DHF has a powerful potential on synchronized neuronal discharges which should be considered in future therapeutical approaches.

Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice.

Brain Derived Neurotropic Factor (BDNF) is a neutrophic factor that is required for the normal neuronal development and function. BDNF is involved in regulation of synapses as well as neuronal excitability. Entorhinal Cortex (EC) is a key brain area involved in many physiological and pathological processes. In this study we investigated the effects of chronically reduced BDNF levels on layer 3 pyramidal neurons of EC. We aimed to assess the effects of reduced levels of BDNF on firing properties, spontaneous synaptic currents and excitation/inhibition balance from acute brain slices. Patch clamp recordings were obtained from pyramidal neurons of Entorhinal Cortex Layer 3. Findings of BDNF heterozygous (BDNF (+/-)) mice compared to their wild-type littermates at the age of 23-28 days. Action potential threshold was shifted (p = 0,002) to depolarized potentials and spike frequency was smaller in response to somatic current injection steps in BDNF (+/-) mice. Spontaneous synaptic currents were also affected. sEPSC amplitude (p = 0,009), sIPSC frequency (p = 0,001) and sIPSC amplitudes (p = 0,023) were reduced in BDNF (+/-). Decay times of sIPSCs were longer in BDNF (+/-) (p = 0,014). Calculated balance of excitatory/inhibitory balance was shifted in the favor of excitation in BDNF (+/-) mice (p = 0,01). These findings suggest that reductions in concentrations of BDNF results in altered status of excitability and excitation/inhibition imbalance. However, these differences observed in BDNF (+/-) seem to have opposing effects on neuronal activity.

Endoplasmic reticulum stress in the livers of BDNF heterozygous knockout mice.

Context: Involvement of endoplasmic reticulum (ER) stress and brain-derived neurotrophic factor (BDNF) in hepatic lipid metabolism has been reported previously. Objective: The effects of chronic BDNF deficiency on ER stress response in the livers were examined in this study. Methods: BDNF(+/-) mice, characterised by BDNF deficiency, and their wild-type (WT) littermates were used. The ER stress was induced by tunicamycin (Tm) (0.5 mg/kg, intraperitoneal). Animals were divided into four groups; WT, WT + Tm, BDNF(+/-), and BDNF(+/-)+Tm. Results: At the basal conditions, BDNF deficiency did not affect hepatic cell death or lipid accumulation. However, during ER stress, BDNF(+/-)+Tm group showed increased apoptosis, GADD153 immunostaining, sterol regulatory element-binding protein-1c (SREBP-1c) level, and steatosis compared to the WT + Tm group. Conclusion: Endogenous BDNF might be protective against apoptosis through GADD153 suppression and steatosis via SREBP-1c suppression during ER stress. This effect of BDNF might be clinically important for type 2 diabetes and obesity, which are related with both ER stress and BDNF deficiency.

Renal response to tunicamycin-induced endoplasmic reticulum stress in BDNF heterozygous mice.

BACKGROUND: The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported. OBJECTIVES: The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress. MATERIAL AND METHODS: Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/-)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/-), WT+Tm, and BDNF(+/-)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function. RESULTS: Circulating and tissue BDNF levels were significantly lower in the BDNF(+/-) and BDNF(+/-)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/-)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/-)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/-)+Tm (p < 0.05) groups. CONCLUSIONS: This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.

Impaired GABAergic inhibition in the visual cortex of brain-derived neurotrophic factor heterozygous knockout mice.

Brain derived neurotrophic factor (BDNF) promotes the formation, maturation and stabilization of inhibitory synapses in the central nervous system. In addition, BDNF has been suggested to regulate the critical period for ocular dominance plasticity in the visual system. Here we further evaluated the role of BDNF in the visual cortex by studying the GABAergic synaptic transmission under conditions of chronically reduced levels of BDNF. Whole-cell patch-clamp recordings were performed from pyramidal neurons located in layers II/III of visual cortical slices in heterozygous BDNF knockout mice (BDNF (+/-)) and their wild-type littermates at the age of 21-25 days. The BDNF (+/-) mice showed a decreased frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) as well as a reduced amplitude and prolonged decay time constant of evoked IPSCs. Further analyses indicated an impaired presynaptic GABAergic function in BDNF (+/-) mice, as shown by the decreased release probability, steady-state release and synchronous release of GABA. However, the number of functional release sites remained unchanged. In line with these observations, an impaired glutamate-driven GABA release was observed in BDNF (+/-) mice. Furthermore, the overall balance in the strength of cortical excitation to inhibition shifted towards a decreased inhibition. Finally, the reversal potential for chloride-mediated evoked IPSCs was not affected. These findings suggested that chronically reduced levels of BDNF strongly impair the GABAergic inhibitory function in visual cortex by altering postsynaptic properties and by reducing presynaptic GABA release as well as the overall strength of inhibition onto pyramidal neurons within the cortical network. These impairments of inhibitory function are compatible with a rather immature status of the GABAergic system in BDNF (+/-) mice, which supports the hypothesis that the level of expression for BDNF critically affects maturation and function of the GABAergic inhibition.

Brain-derived neurotropic factor (BDNF) heterozygous mice are more susceptible to synaptic protein loss in cerebral cortex during high fat diet.

In this study we aimed to investigate whether reduced BDNF levels aggravate the susceptibility of the brain to hazardous effects of high fat diet. For this purpose, we fed BDNF heterozygous mice and wild type littermates with normal and high fat diet for 16 weeks. Concentrations of two synaptic proteins (SNAP-25 and PSD-95) and oxidative stress parameters (MDA, SOD, CAT) were evaluated in the cortex after diet period. Interestingly, body weights of BDNF heterozygous groups fed with control diet were higher than their littermates and heterozygous mice fed with HFD were the heaviest in all experimental groups. MDA levels were significantly elevated in both HFD groups (wild type and BDNF(+/-)). Synaptic markers PSD-95 and SNAP-25 markedly decreased in BDNF(+/-) group fed with HFD compared to other groups. In conclusion, we suggest that endogenous BDNF has an important and possibly protective role in diet-induced changes in the cortex.

The effect of chronic restraint stress and sulfite on visual evoked potentials (VEPs): relation to lipid peroxidation.

Stress and sulfite can stimulate numerous pathways leading to an increased production of free radicals which generate a peroxidation cascade producing lipid peroxidation, protein oxidation, DNA damage and cell death, and contribute to the occurrence of pathologic conditions. The purpose of our study was to investigate the effects of stress and sulfite on visual evoked potentials (VEPs) and to examine the relationship between lipid peroxidation and VEP changes. Forty male wistar rats, aged three months were used. They were equally divided into four groups: control (C), the group exposed to restraint stress (R), the group treated with sulfite (S) and the group exposed to stress and treated with sulfite (RS). Chronic restraint stress was applied for 21 days (1h/day) and sodium metabisulfite (520 mg/kg/day) was given by gavage for the same period. All latencies of VEP components were prolonged in the R, S and RS groups with respect to the C group. Brain and retina TBARS levels were found to be increased in those groups compared to the C group. Our results strongly suggest that the latency prolongations of all VEP components may have resulted from the enhancement of lipid peroxidation. Correlation analysis between brain and retina TBARS levels and VEP latencies also support this conclusion. Our data in regard to latency prolongations of all VEP components in the stress group exposed to sulfite, reflected an additive effect of sulfite toxicity on VEP components. Therefore it could be suggested that chronic exposure to stress and sulfite together is associated with a considerable health risk.

Electrophysiological evidence on epileptiform activity enhanced by electrical stimulation of teeth in rats.

The aim of this study was to evaluate the possible effects of electrical stimulation (ES) of tooth on penicillin-induced epileptiform activity in rats. Experiment was realized on 24 adult male Sprague Dawley rats. Rats were assigned three groups [stimulation group (SG), penicillin group (PG), and penicillin+stimulation group (PSG)]. In SG, ES was only applied. Ten pulses of electrical current were delivered to the teeth for a duration of 2 milliseconds at 1-second intervals from a stimulator. Currents were applied in the range of 40-240 µA with 40 µA steps. Electrocorticography (ECoG) recordings were taken before and after ES. In PG, ECoG recordings were taken before and during the injection of penicillin. In PSG, after epileptiform activity was induced, ES was applied and ECoG recordings were taken as in SG. All the data were analyzed with Student's t test. Applied currents did not cause any epileptiform activity in SG. When the PSG was compared with the PG it was seen that the spike frequency of epileptiform activity increased in a statistically significant way after application of 240 µA (P < 0·05). On the other hand current application caused an increase in the spike amplitude of the PSG compared with the amplitude of the PG, but it was not statistically significant. We concluded that ES of tooth with high current can trigger epileptiform activity in rats. For this reason, further research is required to evaluate the effects of ES of tooth for pulp testing on epileptic human subjects and antiepileptic drug users.