Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease.

Increasing evidence suggests that elevated intracellular levels of reactive oxygen species (ROS) play a significant role in the pathogenesis of many diseases. Increased intracellular levels of ROS can lead to the oxidation of lipids, DNA, and proteins, contributing to cellular damage. Hence, the maintenance of redox hemostasis is essential. Naringenin (NAR) is a flavonoid included in the flavanones subcategory. Various pharmacological actions have been ascribable to this phytochemical composition, including antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, antiadipogenic, neuro-, and cardio-protective activities. This review focused on the underlying mechanism responsible for the antioxidative stress properties of NAR and its' nanoformulations. Several lines of in vitro and in vivo investigations suggest the effects of NAR and its nanoformulation on their target cells via modulating signaling pathways. These nanoformulations include nanoemulsion, nanocarriers, solid lipid nanoparticles (SLN), and nanomicelle. This review also highlights several beneficial health effects of NAR nanoformulations on human diseases including brain disorders, cancer, rheumatoid arthritis, and small intestine injuries. Employing nanoformulation can improve the pharmacokinetic properties of NAR and consequently efficiency by reducing its limitations, such as low bioavailability. The protective effects of NAR and its' nanoformulations against oxidative stress may be linked to the modulation of Nrf2-heme oxygenase-1, NO/cGMP/potassium channel, COX-2, NF-κB, AMPK/SIRT3, PI3K/Akt/mTOR, BDNF, NOX, and LOX-1 pathways. Understanding the mechanism behind the protective effects of NAR can facilitate drug development for the treatment of oxidative stress-related disorders.

Motor Dysfunction of Gastric Antral Smooth Muscle in Diabetic Rats: Contribution of ATP-Dependent Potassium Channels.

Background: The goal of the current research was to further elucidate the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in the motility and contractility force of gastric smooth muscle of diabetic rats. Materials and Methods: Male Wistar rats (190-230 g) were grouped into control and streptozotocin (STZ)-induced diabetes (55 mg/kg) rats. Thirty days later, gastric muscle contractility was measured using a myograph and a force transducer of antral segments immersed in a tissue bath. Gastric emptying response was measured through feeding of standard pellet. Furthermore, the expression of KATP channel subunits in antral smooth muscle was determined by western blot technique. Results: The amplitude of KCl-evoked twitch contractions of diabetic antral strips was about 25% more than control (P < 0.05). Application of minoxidil, a KATP channel opener, dose dependently decreased the force of twitch contractions in both normal and diabetic antral strips. Application of 10 µM glibenclamide, a KATP channel blocker, did not antagonize the minoxidil-induced relaxation of antral strips. Diabetic gastric emptying was faster than normal, although not significant. Despite the relaxant effect of minoxidil on gastric emptying rate in normal rats (P < 0.05), this effect was not observed in diabetic rats. Also, glibenclamide increased gastric emptying and antagonized minoxidil-induced relaxation in normal rats (P < 0.05). Furthermore, the expression of KATP Kir6.1 and SUR2B subunits was substantially reduced in antral smooth muscle in diabetic condition (P < 0.01). Conclusion: These results propose that KATP channels may contribute to the development of gastric motility disorders in diabetes.

Alterations in expression of α1-adrenergic receptors possibly are involved in prevention of age-associated apoptosis in rat hippocampus by treadmill exercise.

OBJECTIVES: Exercise is assumed to attenuate age-related neuronal apoptosis, but the detailed mechanism(s) is not fully understood. α1-Adrenergic receptors (ARs) can either trigger or suppress apoptosis, therefore, here we determined the impact of treadmill exercise on the expression of the apoptosis regulatory proteins as well as α1-AR subtypes α1A- and α1B-ARs, in order to elucidate a possible association between apoptosis and the hippocampal expression of α1-ARs in aged male rats. METHODS: Twenty-one male Wistar rats were divided into 3 groups (n=7): young control, aged sedentary, and aged + exercise. Western blot for α1A- and α1B-ARs as well as pro-(Bax and p53) and anti-apoptotic (Bcl2) proteins was conducted. An 8-week regular moderate-intensity treadmill exercise intervention was carried out in exercise group. RESULTS: In aged rats, α1A-AR expression in the hippocampus was significantly increased, and exercise markedly prevented this event. While α1B-AR expression was no altered with aging, a marked reduction in α1B-AR level was detected in exercise group when compared to aged group. Furthermore, pro-apoptotic protein levels of Bax and p53 were upregulated and anti-apoptotic protein Bcl2 was downregulated in the aging hippocampus, but could be reversed by treadmill exercise. In the present research, exercise-induced reduction in α1A- and α1B-ARs was associated with an obvious downregulation of Bax/Bcl2 ratio in aged rats, suggesting that exercise may inhibit apoptosis through regulating α1-ARs, particularly α1A-AR. CONCLUSIONS: Our study suggests that manipulations attenuating α1-AR activity, including nonselective α1-adrenergic antagonists, may protect against hippocampal neurodegeneration in aging brains.

Changes in Protease-Activated Receptor and Trypsin-1 Expression Are Involved in the Therapeutic Effect of Mg2+ Supplementation in Type 2 Diabetes-Induced Gastric Injury in Male Adult Rats.

Purpose: Gastric inflammation is common and usually severe in patients with type 2 diabetes mellitus (T2DM). Evidence suggests protease-activated receptors (PARs) are a link between inflammation and gastrointestinal dysfunction. Given that magnesium (Mg2+) deficiency is a highly prevalent condition in T2DM patients, we assessed the therapeutic role of Mg2+ on the factors involved in gastric inflammation in T2DM. Methods: A rat model of T2DM gastropathy was established using a long-term high-fat diet + a low dose of streptozocin. Twenty-four rats were divided into control, T2DM , T2DM + insulin (positive control), and T2DM + Mg2+ groups. At the end of 2-month therapies, changes in the expression of gastric trypsin-1, PAR1, PAR2, PAR3, PI3K/Akt, and COX-2 proteins were measured by western blot. Hematoxylin and eosin and Masson's trichrome staining were used to detect gastric mucosal injury and fibrosis. Results: The expression of trypsin-1, PAR1, PAR2, PAR3, and COX-2 increased in diabetes, and Mg2+/insulin treatment strongly decreased their expression. The PI3K/p-Akt significantly decreased in T2DM, and treatment with Mg2+/insulin improved PI3K in T2DM rats. Staining of the gastric antrum tissue of the insulin/Mg2+-treated T2DM rats showed a significantly minimal mucosal and fibrotic injury compared with those of rats from the T2DM group. Conclusion: Mg2+ supplement, comparable to insulin, via decreasing PARs expression, mitigating COX-2 activity, and decreasing collagen deposition could exert a potent gastroprotective effect against inflammation, ulcer, and fibrotic development in T2DM patients.

Alleviation of cholestatic liver injury and intestinal permeability by lubiprostone treatment in bile duct ligated rats: role of intestinal FXR and tight junction proteins claudin-1, claudin-2, and occludin.

Gut barrier disintegrity and endotoxin translocation to the liver and systemic circulation are serious clinical complications associated with the stoppage of intestinal bile flow. There is no precise pharmacological option to prevent increased intestinal permeability after bile duct ligation (BDL). Lubiprostone, a chloride channel-2 agonist, has been shown to accelerate restoration of epithelial barrier dysfunction caused by injury, but the exact mechanisms underlying the beneficial effects of lubiprostone on intestine barrier integrity remain unknown. Here, we assessed the beneficial effect of lubiprostone on cholestasis caused by BDL and relevant mechanisms. Male rats were subjected to BDL for 21 days. Seven days after BDL induction, lubiprostone was administered twice daily (10 µg/kg of body weight). Intestinal permeability was assessed through measurements of serum lipopolysaccharide (LPS) concentration. Real-time PCR was conducted to assess expression of intestinal claudin-1 occludin and FXR genes, which are important in preserving the intestinal epithelial barrier integrity, as well as claudin-2 being involved in a leaky gut barrier. Histopathological alterations were also monitored for liver injury. Lubiprostone significantly decreased BDL-induced systemic LPS elevation in rats. BDL induced a significant reduction in FXR, occludin, and claudin-1 genes expression, while increased claudin-2 expression in rat colon. Treatment with lubiprostone significantly restored expression of these genes to the control values. BDL also increased the level of hepatic enzymes ALT, ALP, AST, and total bilirubin, while lubiprostone could preserve the hepatic enzymes and total bilirubin in the treated BDL rats. Lubiprostone also caused a significant reduction in BDL-induced liver fibrosis and intestinal damage in rats. Our results suggest that lubiprostone favorably prevents BDL-induced alterations in intestinal epithelial barrier integrity possibly via modulating intestinal FXRs and tight junction gene expression.

Exercise may alleviate age-related spatial memory impairment by rescuing ß-adrenergic receptor dysregulation via both G protein-dependent and ß-arrestin-dependent mechanisms in rat hippocampus.

Hippocampal-dependent memory abilities including spatial memory decline with age. Exercise improves memory decline in aging brain, but, the precise mechanisms are still unknown. Learning and memory are recently hypothesized to be mediated by a ß-arrestin (ßArr)-dependent ß-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of ß-adrenergic receptors (ß-ARs; members of the G protein-coupled receptor family), and ßArrs as well as spatial learning and memory in aged male rats to determine whether ß-AR/ßArr pathway could be involved in age-related memory decline. A total of 24 young (3-month-old) and aged (18-month-old) male Wistar rats were divided into young control, aged sedentary, and aged + exercise (n = 8 for each). Western blot for ß1- and ß2-ARs as well as ßArr1 and ßArr2 was performed. Spatial learning and memory were evaluated with the Morris water maze. The results showed significant up-regulation of ß1-ARs as well as significant down-regulation of ß2-AR and ßArrs (ßArr1 and ßArr2) in the hippocampus of aged rats. Spatial memory, but not spatial learning, was impaired in aging, and treadmill exercise improved it. Notably, the improvement in spatial memory was accompanied by amelioration of ß-ARs dysregulation and increase in ßArr2 levels after exercise. There was a negative association between the expression of ßArr2 and ß1-AR, but not ß2-AR, such that an increase in ßArr2 by exercise was associated with reduced ß1-AR expression, suggesting ßArr2 may contribute to posttranslational down-regulation of ß1-ARs. These data suggest that both G protein-dependent and ß-arrestin-dependent ß-AR pathways may regulate spatial learning and memory in aging brain.

Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats.

OBJECTIVES: Dopamine neurotransmission is implicated in multiple neuropsychiatric disorders, most strikingly in Parkinson's disease, bipolar disorder, attention-deficit hyperactivity disorder and schizophrenia. In addition to canonical pathway, D2-receptor (D2R) exerts some of its biological actions through regulating the activity of Akt and GSK3, which in turn were found to be altered in several psychiatric illnesses. The present study examined the impacts of maternal separation, an early-life stress model which has been associated with disturbed neurodevelopment and appearance of many psychiatric disorders, on developmental changes in dopamine concentration and the expression of D2Rs, Akt and GSK-3ß in the medial prefrontal cortex (PFC; a key target of stress) in adolescent and young adult male rats. METHODS: Maternal separation was performed 3 h per day from postnatal days 2 to 11. The PFC protein and dopamine contents were determined using western blotting analysis and Eliza, respectively. RESULTS: Results indicated long-term increases in the prefrontal dopamine levels in stressed adolescent and young adult male rats, accompanied by significant downregulation of D2R as well as upregulation of p-Akt and GSK-3ß contents in stressed adolescence compared to controls, with all protein levels that returned to control values in stressed adult rats. CONCLUSIONS: Our findings suggest that early-life stress differentially modulates prefrontal D2R/Akt/GSK-3ß levels during development. Since adolescence period is susceptible to the onset of specific mental illnesses, disruption of noncanonical components of D2R signaling during this critical period may have an important role in programming neurobehavioral phenotypes in adulthood and manipulations influencing Akt/GSK-3ß pathway may improve the expression of specific dopamine-related behaviors and the effects of dopaminergic drugs.

Anxiety and hippocampal neuronal activity: Relationship and potential mechanisms.

The hippocampus has been implicated in modulating anxiety. It interacts with a variety of brain regions, both cortical and subcortical areas regulating emotion and stress responses, including prefrontal cortex, amygdala, hypothalamus, and the nucleus accumbens, to adjust anxiety levels in response to a variety of stressful conditions. Growing evidence indicates that anxiety is associated with increased neuronal excitability in the hippocampus, and alterations in local regulation of hippocampal excitability have been suggested to underlie behavioral disruptions characteristic of certain anxiety disorders. Furthermore, studies have shown that some anxiolytics can treat anxiety by altering the excitability and plasticity of hippocampal neurons. Hence, identifying cellular and molecular mechanisms and neural circuits that regulate hippocampal excitability in anxiety may be beneficial for developing targeted interventions for treatment of anxiety disorders particularly for the treatment-resistant cases. We first briefly review a role of the hippocampus in fear. We then review the evidence indicating a relationship between the hippocampal activity and fear/anxiety and discuss some possible mechanisms underlying stress-induced hippocampal excitability and anxiety-related behavior.

Prenatal stress and increased susceptibility to anxiety-like behaviors: role of neuroinflammation and balance between GABAergic and glutamatergic transmission.

Neuroplasticity during the prenatal period allows neurons to regenerate anatomically and functionally for re-programming the brain development. During this critical period of fetal programming, the fetus phenotype can change in accordance with environmental stimuli such as stress exposure. Prenatal stress (PS) can exert important effects on brain development and result in permanent alterations with long-lasting consequences on the physiology and behavior of the offspring later in life. Neuroinflammation, as well as GABAergic and glutamatergic dysfunctions, has been implicated as potential mediators of behavioral consequences of PS. Hyperexcitation, due to enhanced excitatory transmission or reduced inhibitory transmission, can promote anxiety. Alterations of the GABAergic and/or glutamatergic signaling during fetal development lead to a severe excitatory/inhibitory imbalance in neuronal circuits, a condition that may account for PS-precipitated anxiety-like behaviors. This review summarizes experimental evidence linking PS to an elevated risk to anxiety-like behaviors and interprets the role of the neuroinflammation and alterations of the brain GABAergic and glutamatergic transmission in this phenomenon. We hypothesize this is an imbalance in GABAergic and glutamatergic circuits (as a direct or indirect consequence of neuroinflammation), which at least partially contributes to PS-precipitated anxiety-like behaviors and primes the brain to be vulnerable to anxiety disorders. Therefore, pharmacological interventions with anti-inflammatory activities and with regulatory effects on the excitatory/inhibitory balance can be attributed to the novel therapeutic target for anxiety disorders.

Possible involvement of the dopamine D2 receptors of ventromedial hypothalamus in the control of free- and scheduled-feeding and plasma ghrelin level in rat.

OBJECTIVES: We investigated effect of the ventromedial hypothalamus (VMH) dopamine D2 receptor inhibition on food intake and plasma ghrelin following chronic free or scheduled meal with different caloric intakes. METHODS: Male Wistar rats (220-250 g) were fed diets containing free (control) or three scheduled diets of standard, restricted and high-fat for 1 month. The animals stereotaxically received an intra VMH single dose of sulpiride (0.005 µg)/or saline (0.5 µL) before meal time. Thirty minutes later, food intake and circulating ghrelin were measured. RESULTS: Sulpiride significantly reduced food intake and ghrelin concentration in freely fed and scheduled-standard diet (p<0.05), while increased food intake, with ghrelin level on fasted level in scheduled-restricted group (p<0.01) compared to control. Food intake and ghrelin concentration between scheduled-high fat and freely fed or scheduled-standard diets did not show significant changes. CONCLUSIONS: The VMH D2 receptors are possibly involved in controlling scheduled eating behavior, depending on energy balance context.

Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats.

INTRODUCTION: Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABAA receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. METHODS: The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. RESULTS: MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABAA receptor and calcineurin levels, with reduced expression of GABAA receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. CONCLUSIONS: Together, our study suggests that GABAA receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

Negative relationship between brain α1A-AR neurotransmission and ßArr2 levels in anxious adolescent rats subjected to early life stress.

Early-life stress is correlated with the development of anxiety-related behavior in adolescence, but underlying mechanisms remain poorly known. The α1A-adrenergic receptor (AR) is linked to mood regulation and its function is assumed to be regulated by ß-arrestins (ßArrs) via desensitization and downregulation. Here, we investigated correlation between changes in α1A-AR and ßArr2 levels in the prefrontal cortex (PFC) and hippocampus of adolescent and adult male rats subjected to maternal separation (MS) and their relationship with anxiety-like behavior in adolescence. MS was performed 3 h per day from postnatal days 2-11 and anxiety-like behavior was evaluated in the elevated plus-maze and open field tests. The protein levels were examined using western blot assay. MS decreased α1A-AR expression and increased ßArr2 expression in both brain regions of adolescent rats, while induced reverse changes in adulthood. MS adolescent rats demonstrated higher anxiety-type behavior and lower activity in behavioral tests than controls. Decreased α1A-AR levels in MS adolescence strongly correlated with reduced time spent in the open field central area, consistent with increased anxiety-like behavior. An anxiety-like phenotype was mimicked by acute and chronic treatment of developing rats with prazosin, an α1A-AR antagonist, suggesting α1A-AR downregulation may facilitate anxiety behavior in MS adolescent rats. Together, our results indicate a negative correlation between α1A-AR neurotransmission and ßArr2 levels in both adults and anxious-adolescent rats and suggest that increased ßArr2 levels may contribute to posttranslational regulation of α1A-AR and modulation of anxiety-like behavior in adolescent rats. This may provide a path to develop more effective anxiolytic treatments.

Honey protects against chronic unpredictable mild stress induced- intestinal barrier disintegration and hepatic inflammation.

Chronic stress is linked to liver injury by increasing intestinal permeability to lipopolysaccharide (LPS), which in turn can result in systemic and liver inflammation and damage. Beneficial effect of honey in the prevention of liver injury has been shown in previous studies, but mechanisms underlying are still less known. Here, we examined the therapeutic impacts of honey on intestinal nuclear factor-κB (NF-κB; an important regulator of stress-induced immune and inflammatory responses) and ileal tight junction (TJ) proteins of claudin-1 and ZO-1, serum LPS, liver inflammation and oxidative markers of malondialdehyde (MDA), nitric oxide (NO), (erythroid-derived 2)-like 2 (Nrf2), tumor necrosis factor (TNF)-α and total antioxidant capacity (TAC) following chronic unpredictable mild stress (CUMS) using Western blotting, ELISA kit and spectrophotometry. Male rats were subjected to CUMS for 28 consecutive days. Honey (0.2 and 2 g/kg/day, by gavage) was administered pretreatment (10 days) and during stress. Honey reduced stress-induced LPS elevation by preventing reduction in the intestinal TJ proteins of claudin-1 and ZO-1, while did not affect NF-kB levels. In liver, honey significantly suppressed stress-induced increase in MDA, NO, TNF-α and Nrf2 expression and normalized TAC. Noteworthy, honey high-dose provoked a greater decrease in TNF-α, Nrf2 and LPS levels than honey low-dose. Together, our study indicated that honey protects against stress-induced liver damage by modulating at least two pathways; intestinal barrier protection via increased TJ protein complex expression, and hepatic TAC protection that may be involved in the inhibition of MDA, NO, TNF-α and Nrf2 expression.

Norepinephrine, neurodevelopment and behavior.

Neurotransmitters play critical roles in the developing nervous system. Among the neurotransmitters, norepinephrine (NE) is in particular postulated to be an important regulator of brain development. NE is expressed during early stages of development and is known to regulate both the development of noradrenergic neurons and the development of target areas. NE participates in the shaping and the wiring of the nervous system during the critical periods of development, and perturbations in this process can alter the brain's developmental trajectory, which in turn can cause long-lasting and even permanent changes in the brain function and behavior later in life. Here we will briefly review evidence for the role of noradrenergic system in neurodevelopmental processes and will discuss about the potential disruptors of noradrenergic system during development and their behavioral consequences.

Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats.

Objective. Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats.Methods. Thirty two male Wistar rats (200-220g) were randomly divided into: control, VitC, CIS, and CIS + VitC groups. Animals received VitC (500 mg/kg/day)/saline by gavage for 3 weeks. For 24 h cumulative and post 18-20 h fasting food intake, fasting plasma ghrelin level, and body weight were measured. Gastric histopathology was also evaluated.Results. Results showed a marked increase in fasting plasma ghrelin and food intake in stressed rats compared to controls. VitC prevented the increases in stressed rats. Histological assessment indicated a positive effect of VitC on gastric glandular cells compared to control, an effect that might partially be a reason of significant increase of plasma ghrelin levels in VitC rats. Elevated plasma ghrelin in VitC group was even higher than that one in stressed group, whereas there were no significant changes in the food intake. Assessment of the percentage of changes in body weight during 21 days showed a significant increase in stressed rats compared to controls. Vitamin C treatment prevented this increase. Stressed rats also displayed depression-like behavior as indicated by sucrose test, whereas VitC ameliorated it.Conclusions. The data of the present study indicate that VitC may overcome ghrelin-induced hyperphagia and improve the abnormal feeding and depressive behavior in CIS rats.

Mechanisms underlying anticonvulsant and proconvulsant actions of norepinephrine.

Norepinephrine (NE) has been shown to exert a potent suppressant effect on seizure development. On the other hand, several lines of evidence have shown that increased NE level is proconvulsant under certain conditions. These data suggest that variations in NE levels could affect modulatory action of noradrenergic system on seizures. Less, however, is known about the mechanisms by which adrenergic pathways protect against seizures or promote seizures. Knowing the mechanisms involved in anti- or proconvulsive effects of NE may help to the development of new therapeutic candidates for patients with refractory epilepsy. Here, we present some possible mechanisms involved in actions of NE on seizures.

Epilepsy-associated alterations in hippocampal excitability.

The hippocampus exhibits a wide range of epilepsy-related abnormalities and is situated in the mesial temporal lobe, where limbic seizures begin. These abnormalities could affect membrane excitability and lead to overstimulation of neurons. Multiple overlapping processes refer to neural homeostatic responses develop in neurons that work together to restore neuronal firing rates to control levels. Nevertheless, homeostatic mechanisms are unable to restore normal neuronal excitability, and the epileptic hippocampus becomes hyperexcitable or hypoexcitable. Studies show that there is hyperexcitability even before starting recurrent spontaneous seizures, suggesting although hippocampal hyperexcitability may contribute to epileptogenesis, it alone is insufficient to produce epileptic seizures. This supports the concept that the hippocampus is not the only substrate for limbic seizure onset, and a broader hyperexcitable limbic structure may contribute to temporal lobe epilepsy (TLE) seizures. Nevertheless, seizures also occur in conditions where the hippocampus shows a hypoexcitable phenotype. Since TLE seizures most often originate in the hippocampus, it could therefore be assumed that both hippocampal hypoexcitability and hyperexcitability are undesirable states that make the epileptic hippocampal network less stable and may, under certain conditions, trigger seizures.

Decrease of high voltage Ca2+ currents in the dentate gyrus granule cells by entorhinal amyloidopathy is reversed by calcium channel blockade.

In the Alzheimer's disease (AD), entorhinal-hippocampal circuit is one of the earliest affected networks. There are some evidences indicating abnormal neuronal excitability and impaired synaptic plasticity in the dentate gyrus (DG) of AD animal model. However, the underlying mechanism leading to DG dysfunction particularly in the early phase of AD is not known. Since calcium dyshomeostasis has a critical role in the etiology of AD, it is possible that this phenomenon precedes electrophysiological alteration in the DG. Here, the effect of the amyloid pathogenesis in the entorhinal cortex (EC) on high activated Ca2+ currents in the DG granule cells was investigated. One week after bilaterally injection of amyloid beta (Aß) 1-42 into the EC, Ca2+ currents in the DG granule cells were assessed by whole cell patch clamp. Voltage clamp recording showed the amplitude of high voltage calcium currents in the DG granule cells was decreased following EC amyloidopathy. However, the Ca2+ current decay was slower than control. Double-pulse recording revealed that Ca2+-dependent inactivation of calcium current (CDI) was more pronounced in the EC-Aß group compared to the control group. However, chronic treatment by calcium channel blocker (CCBs), isradipine or nimodipine, reverse the Ca2+ currents toward the control level. On the other hand, there was no significant difference in the calbindin level in the DG of different groups. In conclusion, our results suggest that Aß in the EC independent of calbindin level triggers a decreased Ca2+ currents along with increased CDI in the DG granule cells which may lead to further electrophysiological alterations in these cells, and treatment by CCBs could preserve normal calcium current and may ultimately normal function against the Aß toxicity.

Calcium channel blockade attenuates abnormal synaptic transmission in the dentate gyrus elicited by entorhinal amyloidopathy.

Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Aß) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Aß treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Aß treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Aß in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Aß toxicity.