Hippocampal Brain-derived Neurotrophic Factor Levels Research Articles

Cognitive Dysfunction in a Mouse Model of Cerebral Ischemia Influences Salivary Metabolomics.

Vascular dementia, caused by cerebrovascular disease, is associated with cognitive impairment and reduced hippocampal metabolite levels. Specifically, cognitive impairment can be induced by decreased hippocampal brain-derived neurotrophic factor (BDNF) expression. The development of low or non-invasive biomarkers to characterize these diseases is an urgent task. Disturbance of metabolic pathways has been frequently observed in cognitive impairment, and salivary molecules also showed the potentials to reflect cognitive impairment. Therefore, we evaluated salivary metabolic profiles associated with altered hippocampal BDNF expression levels in a cerebral ischemia mouse model using metabolomic analyses. The effect of tacrine (a cholinesterase inhibitor) administration was also examined. The arteries of ICR mice were occluded with aneurysm clips to generate the cerebral ischemia model. Learning and memory performance was assessed using the elevated plus maze (EPM) test. Hippocampal and blood BDNF levels were quantified using an enzyme-linked immunosorbent assay. Glutamate decarboxylase 1 (GAD1) mRNA expression, is associated with cognitive impairment, was quantified by a real-time polymerase chain reaction. The EPM test revealed impaired spatial working memory in the cerebral ischemia mouse model; tacrine administration ameliorated this memory impairment. Cerebral ischemia suppressed GAD1 expression by decreasing hippocampal BDNF expression. In total, seven salivary metabolites, such as trimethylamine N-oxide and putrescine, were changed by cognitive impairment and tacrine administration. Our data suggest that salivary metabolite patterns were associated with cognitive function.

Effect of Nucleus Basalis Magnocellularis Lesions on Memory and Hippocampal Brain-Derived Neurotrophic Factor, IL-1β, Glucose, and Corticosterone Levels in Adult Rats

Background: The nucleus basalis magnocellularis (NBM) sends projections to the hippocampus that are implicated in learning and memory formation. Despite ample evidence proposing that cognitive function impairment related to neurodegeneration, it may result from alteration of biochemical substances. We aimed to investigate the effects of NBM lesions on the hippocampal interleukin-1beta (IL-1β), brain-derived neurotrophic factor (BDNF), and corticosterone levels, as inflammation markers, and hallmarks of neurodegeneration, stress, and metabolic status. Methods: Thirty-six male Wistar rats were randomly put in control, sham, and NBM-lesioned groups. After inducing the lesion using an intra-NBM injection of 10 μg ibotenic acid (5 μg/μL, each side) in rats, memory was estimated using the passive avoidance test. Moreover, serum and hippocampal IL-1β levels, as well as the hippocampal corticosterone, BDNF, and glucose levels were measured after 42 days. Results: Findings indicated a significant impairment of retention at different intervals in the NBM-lesioned group. BDNF decreased whereas corticosterone, glucose, and IL-1β levels increased in the hippocampus. Also, the levels of serum IL-1β, hippocampal BDNF, corticosterone, and glucose had significant correlations with hippocampal IL-1β levels. Conclusion: The synchronous alterations of some hippocampal factors, including BDNF, corticosterone, IL-1β, and glucose, caused by NBM lesion suggest that their interaction might play a significant role in neurodegeneration and relevant learning and memory impairments.

Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling.

Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).

The long-term bio-behavioural effects of juvenile sildenafil treatment in Sprague-Dawley versus flinders sensitive line rats.

To investigate the long-term effects of juvenile sub-chronic sildenafil (SIL) treatment on the depressive-like behaviour and hippocampal brain-derived neurotrophic factor (BDNF) levels of adult Sprague-Dawley (SD) versus Flinders Sensitive Line (FSL) rats. SD and FSL rats were divided into pre-pubertal and pubertal groups, whereafter 14-day saline or SIL treatment was initiated. Pre-pubertal and pubertal rats were treated from postnatal day 21 (PND21) and PND35, respectively. The open field and forced swim tests (FST) were performed on PND60, followed by hippocampal BDNF level analysis 1 day later. FSL rats displayed greater immobility in the FST compared to SD rats (p < 0.0001), which was reduced by SIL (p < 0.0001), regardless of treatment period. Hippocampal BDNF levels were unaltered by SIL in all treatment groups (p > 0.05). Juvenile sub-chronic SIL treatment reduces the risk of depressive-like behaviour manifesting during young adulthood in genetically susceptible rats.

Robustly High Hippocampal BDNF levels under Acute Stress in Mice Lacking the Full-length p75 Neurotrophin Receptor.

Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation. We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTRExIII-/-) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 (Il6) was assessed with RT-PCR. Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain Il6 mRNA expression irrespective of genotype; however, p75NTRExIII-/- mice showed elevated baseline Il6 expression and thus a lower relative increase. Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related Il6 gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.

Angiotensin IV improves spatial memory in streptozotocin-induced diabetic rats by reducing oxidative stress and altering BDNF levels

In this study, we investigated the protective effects of angiotensin IV (Ang IV) on cognitive function in streptozotocin (STZ)‑induced diabetic rats. Male Wistar albino rats, were randomly divided into four groups; control (C), diabetes (Dia, 60 mg/kg, STZ, i.p.), Ang IV (5 μg/kg, s.c.) and Dia+Ang IV. The passive avoidance and Morris water maze (MWM) tests were used to evaluate learning and memory performance. Behavioral tests were carried out between 21 and 30 days after the initial Ang IV injection. Hippocampi were dissected and retained for biochemical and Western blot analysis. The Dia group exhibited the poorest behavioral results, while the Dia+Ang IV group performed highest on the MWM task. Superoxide dismutase, glutathione peroxidase, and malondialdehyde levels increased significantly in the Dia group compared to Dia+Ang IV. Brain‑derived neurotrophic factor (BDNF) and N‑methyl‑D‑aspartate levels were significantly elevated, while levels of GABAA significantly decreased, in the Dia+Ang IV group compared to the Dia group. These findings suggest that peripheral administration of Ang IV ameliorated spatial memory in diabetic rats by decreasing hippocampal oxidative stress and BDNF levels.

Effects of quercetin on spatial memory, hippocampal antioxidant defense and BDNF concentration in a rat model of Parkinson's disease: An electrophysiological study.

Objective:Quercetin is one of the most popular flavonoid with protective effects against neural damages in Parkinson's disease (PD). We assessed the effect of quercetin administration on memory and motor function, hippocampal ‎ oxidative stress and brain-derived neurotrophic factor (BDNF) level in a 6-OHDA-induced Parkinson's rat model.Material and Methods:The animals were divided into the following five groups (n=8): control, sham-surgery (sham), lesion (PD), and lesion animals treated with quercetin at doses of 10 (Q10) and 25 (Q25) mg/kg. For induction of a model of PD, 6-OHDA was injected into the striatum of rats. The effects of quercetin were investigated on spatial memory, hippocampal BDNF and malondialdehyde (MDA) levels, and total antioxidant capacity (TAC). Spatial memory was assessed by Morris water maze test, and the neuronal firing frequency in hippocampal dentate gyrus (HDG) was evaluated by single-unit recordings.Results:Mean path length and latency time, rotational behavior and hippocampal MDA concentration were significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and hippocampal levels of TAC and BDNF were significantly decreased in the PD group compared to the sham group (p<0.01 to p<0.001). Quercetin treatment significantly enhanced time spent in goal quadrant (p<0.05), swimming speed (p<0.001) and spike rate (p<0.01), improved hippocampal TAC (p<0.05 to p<0.001) and BDNF (p<0.01 to p<0.001) level, and decreased mean path length (p<0.001), latency time (p<0.05 to p<0.001), rotational behavior and hippocampal MDA concentration (p<0.05).Conclusion:The cognitive-enhancing effect of quercetin might be due to its antioxidant effects in the hippocampus.

Brain‑derived neurotrophic factor and nitric oxide contribute to protective effects of rosiglitazone on learning and memory in hypothyroid rats.

The effects of the well‑known peroxisome proliferator‑activated receptor gamma (PPAR-γ) agonist rosiglitazone (Rosi) on brain‑derived neurotrophic factor (BDNF), nitric oxide (NO), and learning and memory were investigated in hypothyroid rats. Hypothyroidism was induced in immature Wistar rats by administration of propylthiouracil in drinking water. Rats were divided into four groups: control, hypothyroid, and hypothyroid treated with Rosi at doses of 2 mg/kg or 4 mg/kg. Memory was then assessed by the Morris water maze (MWM) and passive avoidance (PA) tests. Following anesthetization, brain samples were collected for biochemical measurements. Hypothyroidism increased the escape latency and traveled path in the learning trials of the MWM and decreased the time spent and the distance traveled in the target quadrant on the probe day. Hypothyroidism also impaired the avoidance behavior of rats in the PA test. Rosi improved the performance of rats in both MWM and PA tasks. Hypothyroidism also decreased hippocampal BDNF levels, increased NO metabolites, and induced oxidative damage in the brain. Treatment of hypothyroid rats with both doses of Rosi increased BDNF levels and decreased NO metabolites and malondialdehyde concentrations. In addition, thiol content and superoxide dismutase and catalase activities were increased in the brain regions of hypothyroid rats receiving Rosi. The administration of 4 mg/kg Rosi also significantly increased serum thyroxin levels. The results of the present study showed that BDNF and NO play a role in the protective effects of Rosi against learning and memory impairment in hypothyroid rats.

Evaluation of the Effect of Hypericum triquetrifolium Turra on Memory Impairment Induced by Chronic Psychosocial Stress in Rats: Role of BDNF.

BackgroundChronic psychosocial stress impairs memory function and leads to a depression-like phenotype induced by a persistent status of oxidative stress. Hypericum perforatum L. (St. John’s wort) is widely used to relieve symptoms of anxiety and depression; however, its long-term use is associated with adverse effects. Hypericum triquetrifolium Turra is closely related to H. perforatum. Both plants belong to Hypericaceae family and share many biologically active compounds. Previous work by our group showed that methanolic extracts of H. triquetrifolium have potent antioxidant activity as well as high hypericin content, a component that proved to have stress-relieving and antidepressant effects by other studies. Therefore, we hypothesized that H. triquetrifolium would reduce stress-induced cognitive impairment in a rat model of chronic stress.ObjectiveTo determine whether chronic treatment with H. triquetrifolium protects against stress-associated memory deficits and to investigate a possible mechanism.MethodsThe radial arm water maze (RAWM) was used to test learning and memory in rats exposed to daily stress using the resident–intruder paradigm. Stressed and unstressed rats received chronic H. triquetrifolium or vehicle. We also measured levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, cortex and cerebellum.ResultsNeither chronic stress nor chronic H. triquetrifolium administration affected performance during acquisition. However, memory tests in the RAWM showed that chronic stress impaired different post-encoding memory stages. H. triquetrifolium prevented this impairment. Furthermore, hippocampal BDNF levels were markedly lower in stressed animals than in unstressed animals, and chronic administration of H triquetrifolium chronic administration protected against this reduction. No significant difference was observed in the effects of chronic stress and/or H. triquetrifolium treatment on BDNF levels in the cerebellum and cortex.ConclusionH. triquetrifolium extract can oppose stress-associated hippocampus-dependent memory deficits in a mechanism that may involve BDNF in the hippocampus.

The role of brain-derived neurotrophic factor (BDNF) in the development of vascular cognitive impairment

Brain-derived neurotrophic factor (BDNF) is principally involved in the phenomena of neuroplasticity of the brain and long-term synaptic potency (LTP) in the hippocampus. This article covers the role played by BDNF as a diagnostic marker of vascular cognitive disorders. The relationship between etiology and the degree of cognitive impairment with the level of BDNF is ambiguous. Especially if we take into account the fact that vascular pathology can be a trigger for molecular mechanisms of neurodegeneration. The lowest BDNF level can be found among patients with dementia in Alzheimer’s disease, and there is evidence that patients with neurodegenerative disease without cognitive impairment have a decreased BDNF level. Patients with vascular cognitive impairment have a less expressed decrease of BDNF level, although it can depend on severity of stroke. In case of vascular cognitive impairment, it is possible to improve cognitive state thanks to increased BDNF level in hippocampus after physical activity. That opens new opportunities in rehabilitation. Genetic polymorphism of BDNF leads to the problems with cognitive rehabilitation and increases the risk of post-stroke dementia and dementia in Alzheimer’s disease. Supposedly, changes in the structure of BDNF-propeptide, which is involved in the processes of long-term synaptic depression (LTD) of the hippocampus, are the main cause in this case.

Does Aerobic and Resistance Exercise Influence Episodic Memory through Unique Mechanisms?

Aerobic and resistance exercise (acute and chronic) independently and collectively induce beneficial responses in the brain that may influence memory function, including an increase in cerebral blood flow, neurogenesis, neuroelectrical alterations, and protein production. However, whether aerobic and resistance exercise improve memory via similar or distinct mechanisms has yet to be fully explained. Here, we review the unique influence of aerobic and resistance exercise on neural modulation, proteins, receptors, and ultimately, episodic memory. Resistance training may optimize neural communication, information processing and memory encoding by affecting the allocation of attentional resources. Moreover, resistance exercise can reduce inflammatory markers associated with neural communication while increasing peripheral and central BDNF (brain-derived neurotrophic factor) production. Aerobic training increases hippocampal levels of BDNF and TrkB (Tropomyosin receptor kinase B), protein kinases and glutamatergic proteins. Likewise, both aerobic and anaerobic exercise can increase CREB (cAMP response element-binding protein) phosphorylation. Thus, we suggest that aerobic and resistance exercise may influence episodic memory via similar and, potentially, distinct mechanisms.

Long-Term Music Exposure Prevents Age-Related Cognitive Deficits in Rats Independently of Hippocampal Neurogenesis.

Cognitive decline appears across aging. While some studies report beneficial effects of musical listening and practice on cognitive aging, the underlying neurobiological mechanisms remain unknown. This study aims to determine whether chronic (6h/day, 3times/week) and long-lasting (4-8months) music exposure, initiated at middle age in rats (15months old), can influence behavioral parameters sensitive to age effects and reduce age-related spatial memory decline in rats. Spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior as well as spatial working and reference memory were assessed in 14-month-old rats and then after 4 and 8months of music exposure (19 and 23months old, respectively). Spatial learning and reference memory data were followed up by considering cognitive status of animals prior to music exposure (14 months old) given by K-means clustering of individual Z-score. Hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) level in the hippocampus and frontal cortex were measured. Results show that music exposure differentially rescues age-related deficits in spatial navigation tasks according to its duration without affecting spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior. Hippocampal cell proliferation as well as hippocampal and frontal cortex BDNF levels was not affected by music across aging. Cognitive improvement by music in aging rats may require distinct neurobiological mechanisms than hippocampal cell proliferation and BDNF.

Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level

AimsFluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. Main methodsThe sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Key findingsThe present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SignificanceIn conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.

Effects of treadmill exercise and sex hormones on learning, memory and hippocampal brain-derived neurotrophic factor levels in transient congenital hypothyroid rats

Transient thyroid function abnormalities at birth exhibit intellectual developmental and cognitive disorders in adulthood. Given the well-known effects of physical activity and sex hormones on cognitive functions and brain-derived neurotrophic factor (BDNF), the present study examined the effects of treadmill exercise, sex hormones, and the combined treatment on learning and memory and hippocampal BDNF levels in transient congenital hypothyroid rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). From PNDs 28 to 47, female and male pup rats received 17β-estradiol and testosterone, respectively, and about 30 min later, they were forced to run on the treadmill for 30 min once a day. On PNDs 48-55, spatial learning and memory of all rats tested in the water maze, which followed by measurement of BDNF in the hippocampus. Results showed that developmental hypothyroidism induced significant deficits in spatial learning and memory and hippocampal BDNF in both male and female rats. In both male and female hypothyroid rats, exercise and exercise plus sex hormones, but not sex hormones alone alleviated learning and memory deficits and all treatments (exercise, sex hormones, and the combined treatment) increased hippocampal BDNF. These disconnects in the effects of exercise, sex hormones and the combined treatment on behavioral and neurochemical outcomes suggest that a neurochemical mechanism other than hippocampal BDNF might contribute in the ameliorating effects of exercise on learning and memory deficits induced by developmental thyroid hormone insufficiency.

Sex-dependent effects of postweaning exposure to an enriched environment on novel objective recognition memory and anxiety-like behaviors: The role of hippocampal BDNF level.

Exposure to enriched environment (EE) has been indicated to enhance cognitive functions, hippocampal neural plasticity, neurogenesis, long-term potentiation, and levels of the brain-derived neurotrophic factor (BDNF) in laboratory animals. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. This is important because the beneficial effects of EE may be predominant in the adolescence stage. Therefore, the present study was designed to compare the effects of EE during adolescence (PND21-PND60) on novel objective recognition memory (NORM), anxiety-like behaviors, and hippocampal BDNF mRNA level in the adult male and female rats. Assessment of NORM and anxiety-like behaviors has been done by novel objective recognition task, open field (OF), and elevated plus maze (EPM), respectively. The expression of BDNF mRNA level was also evaluated by quantitative RT-PCR. Our findings demonstrated that housing in the EE during adolescence improves NORM in adult male rats. Also, exposure to EE during adolescence had a different effect on anxiety-like behaviors in both sexes. Additionally, our results indicated an augmented BDNF level in the hippocampus of male and female rats. In conclusion, adolescent exposure to EE has sex-dependent effects on cognitive functions and anxiety-like behaviors and increases BDNF mRNA expression in the hippocampus of both male and female rats; thus, BDNF is an important factor that can mediate the beneficial effects of EE and running exercise on cognitive functions and psychiatric traits.

Methylphenidate treatment increases hippocampal BDNF levels but does not improve memory deficits in hypoxic-ischemic rats.

Methylphenidate (MPH) is a stimulant drug mainly prescribed to treat cognitive impairments in attention-deficit/hyperactivity disorder (ADHD). We demonstrated that neonatal hypoxia-ischemia (HI) induced attentional deficits in rats and MPH administration reversed these deficits. However, MPH effects on memory deficits after the HI procedure have not been evaluated yet. We aimed to analyze learning and memory performance of young hypoxic-ischemic rats after MPH administration and associate their performance with brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus. Male Wistar rats were divided into four groups (n=11-13/group): control saline (CTS), control MPH (CTMPH), HI saline (HIS) and HIMPH. The HI procedure was conducted at post-natal day (PND) 7 and memory tasks between PND 30 and 45. MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior to each behavioral session and daily, for 15 days, for the BDNF assay (n=5-7/group). As expected, hypoxic-ischemic animals demonstrated learning and memory deficits in the novel-object recognition (NOR) and Morris water maze (MWM) tasks. However, MPH treatment did not improve learning and memory deficits of these animals in the MWM-and even disrupted the animals' performance in the NOR task. Increased BDNF levels were found in the hippocampus of HIMPH animals, which seem to have been insufficient to improve memory deficits observed in this group. The MPH treatment was not able to improve memory deficits resulting from the HI procedure considering a dose of 2.5 mg/kg. Further studies investigating different MPH doses would be necessary to determine a dose-response relationship in this model.

Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats

Status epilepticus (SE) is a state of prolonged and repeated seizures that can lead to permanent brain damage or life-threatening conditions. Transcranial direct current stimulation (tDCS) non-invasively provides a polarity-specific electric current to modulate brain excitability. Little is known about the therapeutic potential of tDCS in SE. Here, we aim to determine the tDCS effects on seizure severity, EEG and post-SE consequences in rats with kainic acid (KA)-induced SE. Rats were subjected to cathodal tDCS or sham stimulation over the dorsal hippocampus for 5 days. KA was intraperitoneally injected to induce SE. We used continuous video-EEG recording to monitor seizure activity, immunostaining and Timm staining to evaluate neuron counts and mossy fiber sprouting, and ELISA for Brain-derived neurotrophic factor (BDNF) protein measurement. Two featured EEG patterns, gamma ranged high-frequency polyspikes and low-frequency spike-and-wave complexes, were identified in the hippocampal CA1 of KA-induced SE rats. tDCS elicited a significant decrease in severe seizures of Racine stages 4–5 in KA-induced SE rats. tDCS-treated rats manifested diminished high-frequency oscillation during SE, decreased chronic spontaneous spike activities and mossy fiber sproutings compared to sham. tDCS-treated rats also exhibited significantly lower hippocampal BDNF protein levels than sham immediately and 4 weeks after SE. A positive correlation between the hippocampal BDNF level and the seizure severity of SE was found. Altogether, our results show that repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences in KA-induced SE rats, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures.

Continuous environmental enrichment and aerobic exercise improves spatial memory: focus on rat hippocampal BDNF and NGF

Memory is an important cognitive function in humans. Exercise and environmental enrichment (EE) exposure have positive effects on memory function via improved neurogenesis through expression of growth factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Exercise and environmental enrichment have independently been shown to increase BDNF and NGF, but the effect of the combination of these treatments has not been widely studied. This experimental study aims to analyse the effect of aerobic exercise, EE exposure, and combination of aerobic exercise and EE exposure on memory function. This study used twenty 7-month old male Wistar rats that were given treatment for 8 weeks. Memory function was tested using forced alternation Y-maze. Hippocampal expression of BDNF and NGF were also assessed. The results showed the combination group has highest performance in memory function test and also the highest level of hippocampal BDNF and NGF (P&lt;0.05). It can be concluded that the combination of aerobic exercise and continuous EE exposure produces the best results for memory function through higher levels of hippocampal BDNF and NGF in adult rats.

Exogenous GM1 Ganglioside Attenuates Ketamine-Induced Neurocognitive Impairment in the Developing Rat Brain

A prolonged exposure to ketamine triggers significant neurodegeneration and long-term neurocognitive deficits in the developing brain. Monosialotetrahexosylganglioside (GM1) can limit the neuronal damage from necrosis and apoptosis in neurodegenerative conditions. We aimed to assess whether GM1 can prevent ketamine-induced developmental neurotoxicity. Postnatal day 7 (P7) rat pups received 5 doses of intraperitoneal ketamine (20 mg/kg per dose) at 90-minute intervals for 6 hours. Cognitive functions, determined by using Morris water maze (MWM) including escape latency (at P32-36) and platform crossing (at P37), were compared among the ketamine-exposed pups treated with or without exogenous GM1 (30 mg/kg; n = 12/group). The effect of GM1 on apoptosis in hippocampus was determined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining and activated caspase 3 measurement. The hippocampal expression of brain-derived neurotrophic factor (BDNF), along with the phosphorylation of protein kinase B (AKT) and extracellular signal-related kinases 1 and 2 (ERK1/2), was detected by western blotting (n = 6/group). Anti-BDNF antibody (2 μg per rat) administered before GM1 treatment was applied to determine the neuroprotective mechanisms of GM1. The rats receiving ketamine exposure experinced cognitive impairment in MWM test compared to the control rats, indicated by prolonged escape latency at P34 (P = .006), P35 (P = .002), and P36 (P = .005). However, in GM1-pretreated rats, ketamine exposure did not induce prolonged escape latency. The exogenous GM1 increased the platform-crossing times at P37 (3.00 ± 2.22 times vs 5.40 ± 1.53 times, mean ± standard deviation; P = .041) and reduced the hippocampal TUNEL-positive cells and cleaved-caspase 3 expression in ketamine-exposed young rats. Ketamine decreased BDNF expression and phosphorylation of AKT and ERK in the hippocampus, whereas exogenous GM1 blocked these ketamine-caused effects. However, for the ketamine-exposed rat pups receiving exogenous GM1, compared to immunoglobulin Y (IgY) isotype control, the BDNF-neutralizing antibody treatment counteracted the exogenous GM1-induced improvement of the escape latency at P36 (41.32 ± 12.37 seconds vs 25.14 ± 8.97 seconds, mean ± standard deviation; P = .036), platform-crossing times at P37 (2.16 ± 1.12 times vs 3.92 ± 1.97 times, mean ± standard deviation; P < .036), apoptotic activity, as well as AKT and ERK1/2 phosphorylation in the hippocampus of ketamine-challenged young rats. Our data suggest that the exogenous GM1 acts on BDNF signaling pathway to ameliorate the cognitive impairment and hippocampal apoptosis induced by ketamine in young rats. Our study may indicate a potential use of GM1 in preventing the cognitive deficits induced by ketamine in the young per se.

Treadmill exercise restores memory and hippocampal synaptic plasticity impairments in ovalbumin-sensitized juvenile rats: Involvement of brain-derived neurotrophic factor (BDNF)

Studies demonstrate that asthma, especially during childhood, affects the functions of the brain including learning and memory. Exercise is well known for its neuroprotective functions and for its beneficial effects on asthma. We aimed to assess the effects of exercise on cognitive function, synaptic plasticity, and hippocampal brain-derived neurotrophic factor (BDNF) levels in ovalbumin (OVA) sensitized juvenile rats. Rats were sensitized by intraperitoneal administration and inhaled OVA. Animals were subjected to treadmill running exercise during the OVA-challenged period. T-helper type 2 (Th2) cytokine [interleukin (IL)-4], Th1 cytokine (INF-γ) levels, and INF-γ/IL-4 (Th1/Th2) ratio in bronchoalveolar lavage fluid (BALF), and tracheal response to methacholine and OVA were measured. Further, memory behaviors and BDNF levels were measured in the hippocampus as well as long-term potentiation (LTP) was assessed by recording field excitatory postsynaptic potentials (fEPSPs) in the hippocampus. The levels of IL-4 and TGF-β were decreased but INF-γ level and INF-γ/IL-4 ratio increased in the BALF due to exercise in the OVA-sensitized animals. In addition, exercise improved OVA-sensitization induced cognitive impairments, increased BDNF levels, and enhanced hippocampal LTP in OVA-sensitized rats. Exercise is not only effective in the alleviation of airway inflammation by restoring Th1/Th2 cytokines balance, but also is a candidate for improvement of memory and synaptic plasticity deficits partially through increasing the levels of hippocampal BDNF in OVA-sensitized rats.