Alteration of the α5 GABA receptor and 5HTT lead to cognitive deficits associated with major depressive-like behaviors in a 14-day combined stress rat model.

INTRODUCTION: Current models used to study the pathophysiology of major depressive disorder (MDD) are laborious and time consuming. This study examined the effect of a 14-day combined stress model (CS; corticosterone injection and restraint stress) in male Sprague-Dawley rats and also compare the effect of CS versus 28-day corticosterone treatment on depressive-like behaviour and cognitive deficits. MATERIEL AND METHODS: Depressive-like behaviours and cognitive deficits were assessed in the forced swim test (FST), sucrose preference (SPT), Morris water maze (MWM) and novel object recognition (NORT) tests. Real-time PCR and ELISA were respectively used to detect expression of the serotonin transporter (5-HTT), serotonin 1 A receptor (5-HT1A), α5 GABAA receptor, and the concentrations of corticosterone (plasma), GABA and acetylcholinesterase (AChE) in the hippocampus and Prefrontal cortex (PFC).Results CS group showed increased immobility time in the FST, time to reach the MWM platform, higher corticosterone level, and increased expressions of hippocampal and PFC 5-HT1A and α5 GABAA receptors, and AChE compared to their control groups. In contrast, reductions in SPT ratio, discrimination index in NORT, time in target quadrant, and hippocampal 5-HTT expression was noted relative to their control group. Compared to the 28-day corticosterone only group, PFC 5-HT1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABAA receptors, and AChE concentrations were higher in the CS group. CONCLUSION: Our CS model induced depressive-like behaviour with early cognitive deficits in rats affecting both hippocampus and PFC. The CS model may be useful in investigating new and comprehensive treatment strategies for MDD.

Trauma-like exposure alters neuronal apoptosis, Bin1, Fkbp5 and NR2B expression in an amyloid-beta (1-42) rat model of Alzheimer's disease.

Post-traumatic stress disorder (PTSD) is a risk factor in the development and progression of Alzheimer's disease (AD), with unclear underlying mechanisms. Recently, we provided data showing the effect of trauma-like stress on Bin1 and Fkbp5 expression in the prefrontal cortex of Aß(1-42) lesioned animals. This present work sought to expand the study by examining the involvement of the amygdala and hippocampus, in addition to highlighting the role of NR2B in the co-occurrence of trauma-like stress and an Aß AD-like pathology. Trauma-like condition was induced by exposing the animals to footshocks. Aß(1-42) was injected into the hippocampus of the animals to induce AD-like pathology. Cognitive functions were assessed in the Morris water maze (MWM) and novel object recognition tests, after which amygdala and hippocampus tissues were harvested for neurochemical analyses. We found that the combination of footshocks and Aß(1-42) lesion caused a decrease in the number of crossings in the target quadrant of the Morris water maze test, indicating memory deficits. Footshocks caused a further downregulation of Bin1 in the amygdala of Aß(1-42)-lesioned rats. Prior exposure to footshocks downregulated NR2B in the hippocampus of Aß(1-42)-lesioned rats. In addition, a combination of footshocks and Aß(1-42) lesion sustained the upregulation of Fkbp5 in the hippocampus and amygdala. A combination of footshocks and Aß(1-42) lesion increased neuronal apoptosis in the hippocampus and amygdala. In conclusion, exposure to a trauma-like condition may influence AD-like pathology, leading to exaggerated behavioural and molecular changes in the amygdala and hippocampus.

Inescapable footshocks induce molecular changes in the prefrontal cortex of rats in an amyloid-beta-42 model of Alzheimer's disease.

Alzheimer's disease (AD) affects several brain areas, including the prefrontal cortex (PFC) involved in execution, working memory, and fear extinction. Despite these critical roles, the PFC is understudied in AD pathology. People with post-traumatic stress disorder (PTSD) have twice the risk of developing AD, and the underlying mechanisms linking these two diseases are less understood. Here, we investigated the effect of footshock stress on behavioural vis-a-vis molecular changes in the PFC of an amyloid-beta (Aß)-42 lesion rat model of AD. Trauma-like conditions were induced by exposing the animals to several footshocks. AD-like condition was induced via intra-hippocampal injection of Aß-42 peptide. Following Aß-42 injections, animals were tested for behavioural changes using the Open Field Test (OFT) and Y-maze test. The PFC was later harvested for neurochemical analyses. Our results showed an interactive effect of footshocks and Aß-42 lesion on: reduced percentage alternation in the Y-maze test, suggesting memory impairment; reduced number of line crosses and time spent in the centre square of the OFT, indicating anxiogenic responses. Similarly, there was an interactive effect of footshocks and Aß-42 lesion on: increased FK506 binding protein 51 (FKBP5) expression, which can be associated with stress-induced anxiogenic behaviours; and increased neuronal apoptosis in the PFC of the animals. In addition, footshocks, as well as Aß-42 lesion, reduced superoxide dismutase levels and Bridging Integrator-1 (BIN1) expression in the PFC of the animals, which can be linked to the observed memory impairment. In conclusion, our findings indicate that footshocks exaggerate PFC-associated behavioural and molecular changes induced by an AD-like pathology.

Exposure to footshock stress downregulates antioxidant genes and increases neuronal apoptosis in an Aß(1-42) rat model of Alzheimer's disease.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that develops from exposure to trauma, mostly when normal psychological mechanisms fail. Studies have shown that people who have PTSD are susceptible to developing dementia, mostly Alzheimer's disease (AD), suggesting common underlying risk factors in the comorbidity. However, data elucidating links between these conditions is scarce. Here we show that footshock stress exacerbates AD-like pathology. To induce a trauma-like condition, the rats were exposed to multiple intense footshocks followed by a single reminder. This was followed by bilateral intrahippocampal lesions with amyloid-beta (Aß) (1-42), to model AD-like pathology. We found that footshocks increased anxiety behavior and impaired fear memory extinction in Aß(1-42) lesioned rats. We also found a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and an increased expression of Kelch-like ECH-associated protein 1 (Keap1) in the amygdala and hippocampus. Furthermore, oxidative stress level was sustained, which was associated with increased apoptosis in the amygdala and hippocampus. Our finding suggests that AD-like pathology can induce oxidative changes in the amygdala and hippocampus, which can be exaggerated by footshock stress.

Effects of combination antiretroviral drugs (cART) on hippocampal neuroplasticity in female mice.

The incidence of HIV-associated neurocognitive disorder (HAND) continues despite the introduction of combination antiretroviral drugs (cART). Several studies have reported the neurotoxicity of individual antiretroviral drugs (monotherapy), while the common approach for HIV treatment is through cART. Hence, the current study investigated the effects of long-term exposure to cART on cognitive function, oxidative damage, autophagy, and neuroplasticity in the hippocampus of mice. Female Balb/c mice received a once-a-day oral dose of cART composed of emtricitabine + tenofovir disoproxil fumarate or vehicle for 8 weeks. On week 7 of drug administration, all mice were assessed for spatial learning in the Morris water maze (MWM), and then on week 8, mice were sacrificed, and hippocampal tissue dissected from the brain. For biochemical analyses, we measured the concentration of 4-hydroxynonenal, and the expression of autophagic marker LC3B, synaptophysin, and brain-derived neurotrophic factor (BDNF) in the hippocampus. Our results showed that cART exposure increased escape latency in the MWM test. The cART-treated mice also showed increased 4-hydroxynonenal concentration and expression of LC3B. Furthermore, cART treatment decreased the expression of synaptophysin and BDNF. These findings further support the evidence that cART may be neurotoxic and therefore may play a role in the neuropathogenesis of HAND.

The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State.

Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. Such infections cause the immune system to elicit an inflammatory response resulting in the release of cytokines from macrophages. The cytokines such as interleukin (IL)- 1ß, IL-6, and tumour necrosis factor-α (TNF-α) combat the infection in the localized area ultimately spilling over into circulation resulting in elevated cytokine levels. The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a 'leaky' BBB which facilitates cytokines and LPS entry into the central nervous system. The cytokines activate the microglia which release their own cytokines, specifically IL1ß. IL-ß interacts with the brain endothelium resulting in the activation of cyclooxygenase 2 which catalyzes the production of prostaglandin 2 (PGE2). PGE2 enters the hypothalamic region and induces a fever. Abnormally increased IL-1ß levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. Current treatments for febrile seizures present with side effects that are detrimental to health, which fosters the need for an alternative, more affordable treatment with fewer adverse side effects, and 1 that is easily accessible, especially in low income areas that are also affected by other underlying socio-economic factors, in which febrile seizures are of growing concern.

Effects of bromelain on motor responses following intra-medial forebrain bundle 6-OHDA injection in rat model of parkinsonism.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The conventional therapeutic measures which include the widely used L-DOPA therapy, are inefficient especially when dopamine loss is severe, and the physical symptoms are full blown. Since neuroinflammation is a core feature of PD, this raised the question of whether early treatment with an anti-inflammatory agent may provide a more efficient intervention for PD. In this study, we investigated the effect of bromelain (an anti-inflammatory drug) on motor responses and dopamine levels in a parkinsonian rat model. Male Sprague-Dawley rats were lesioned stereotaxically with the neurotoxin 6-OHDA. The anti-inflammatory agent, bromelain (40 mg/kg i.p) was used to treat a subset of the rats prior to or 24 h post 6-OHDA lesion. Locomotor activity was assessed after 6-OHDA injection, using the cylinder and step tests. The cortical and striatal concentrations of dopamine were also measured. 6-OHDA injection resulted in marked motor impairment which was prevented by pretreatment with bromelain prior to the lesion. Also, the injection of 6-OHDA into the medial forebrain bundle resulted in a significant reduction in dopamine concentration in the striatum and PFC. Bromelain treatment did not alter the suppression of cortical and striatal dopamine levels. Pre-treatment with bromelain reduced the motor dysfunction in the parkinsonian rat model of PD. The efficacy of treatment with bromelain does not appear to be via preservation of the dopaminergic system. The efficacy of bromelain in 6-OHDA injected rats still remains unclear.

Triterpene derivative improves the renal function of streptozotocin-induced diabetic rats: a follow-up study on maslinic acid.

Introduction: Reports indicate that oral administration of plant-derived maslinic acid (MA) exhibits hypoglycemic and renoprotective effects in streptozotocin (STZ)-induced diabetic rats. Challenges with triterpenes such as MA include low bioavailabilty which affects treatment efficacy in experimental animals. The goal of this study was to synthesize the MA derivative phenylhydrazine (PH-MA) in an effort to improve the efficacy of MA. Methods: Separate groups of non-diabetic and STZ-induced diabetic rats (n = 6) were anesthetized and the jugular vein cannulated for the infusion of 0.077 M NaCl at 9 mL/h. The bladder was catheterized for collection the urine samples every 30 min. After 30.5 h equilibration period, consecutive 30 min urine collections were made over the subsequent 4 h of 1 h control, 1.5 h treatment, and 1.5 h recovery periods. PH-MA (22 µg/h) and MA (90 µg/h) were added during the treatment periods for analysis of proximal tubular Na+ handling, plasma aldosterone and arginine vasopressin in male Sprague-Dawley rats. Results: Intravenous infusion of PH-MA (22 µg/h) and MA (90 µg/h) significantly (p Ë‚ .05) increased Na+ output, fractional excretion of Na+ (FENa) and lithium (FELi). Interestingly, like MA, PH-MA significantly (p Ë‚ .05) increased glomerular filtration rate (GFR) over the treatment period and decreased plasma aldosterone levels. Our findings indicate that PH-MA inhibited sodium reabsorption in the proximal and distal tubule as shown by increased FENa and low plasma aldosterone levels, respectively. Conclusions: PH-MA is, therefore, a promising multitarget antidiabetic agent that may ameliorate kidney function of diabetic patients at a dose four times lower than the parent compound (MA).

The Effect of Quercetin on Pro- and Anti-Inflammatory Cytokines in a Prenatally Stressed Rat Model of Febrile Seizures.

Febrile seizures are childhood convulsions resulting from an infection that leads to an inflammatory response and subsequent convulsions. Prenatal stress has been shown to heighten the progression and intensity of febrile seizures. Current medications are costly and have adverse effects associated with prolonged use. Quercetin flavonoid exhibits anti-inflammatory, anti-convulsant, and anti-stress effects. This study was aimed to investigate the therapeutic effect of quercetin in a prenatally stressed rat model of febrile seizures. We hypothesized that quercetin will alleviate the effects of prenatal stress in a febrile seizure rat model. On gestational day 13, Sprague-Dawley rat dams were subjected to restraint stress for 1 hour/d for 7 days. Febrile seizures were induced on postnatal day 14 on rat pups by intraperitoneally injecting lipopolysaccharide followed by kainic acid and quercetin on seizure onset. Hippocampal tissue was harvested to profile cytokine concentrations. Our results show that quercetin suppresses prenatal stress-induced pro-inflammatory marker (interleukin 1 beta) levels, subsequently attenuating febrile seizures. This shows that quercetin can be therapeutic for febrile seizures in prenatally stressed individuals.

Post 6-OHDA lesion exposure to stress affects neurotrophic factor expression and aggravates motor impairment.

Chronic exposure to stress amplifies locomotor deficits and exacerbates dopamine neuron loss in an animal model for Parkinson's disease. The release of neurotrophic factors such as glial cell-line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) following neuronal injury attenuates exacerbated degeneration of these neurons. In this study, the neurotoxin 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle of male Sprague Dawley rats. A subset of these rats was subjected to post-lesion restraint stress after which the effect of exposure to stress on locomotor activity (forelimb akinesia test), neurotrophic factor (GDNF and NT-3) and corticosterone concentration was assessed. Exposure to post-lesion stress resulted in increased preference to use the unimpaired forelimb (forelimb ipsilateral to the lesioned hemisphere) in the forelimb akinesia test. The expected increase in both GDNF and NT-3 concentration following injury was not present in the stressed animals. However, both the non-stressed and stressed lesioned groups had decreased neurotrophic factor concentration at one and two weeks post lesion. This decrease was exaggerated in the stressed rats. The decrease in neurotrophic factor concentration was accompanied by an increase in corticosterone concentration in the stressed rats. These findings demonstrate that exposure to post-6-OHDA lesion stress exaggerates dopamine neurodegeneration and enhance motor impairment. This suggests that conditions that result in a hyper-activated hypothalamic-pituitary-adrenal axis such as depression which is concomitant to a Parkinson's disease diagnosis may be responsible for enhanced dopamine depletion by attenuating neurotrophic factor concentration elevation in the nigrostriatal pathway following neuronal injury.

Pre-infection administration of asiatic acid retards parasitaemia induction in Plasmodium berghei murine malaria infected Sprague-Dawley rats.

BACKGROUND: Malaria prevention has remained a critical area in the absence of efficacious vaccines against malaria. Drugs currently used as chemotherapeutics are also used in chemoprophylaxis increasing possible drug resistance. Asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties with emerging anti-malarial potential. The influence of asiatic acid administration prior to Plasmodium berghei infection of Sprague-Dawley rats on parasitaemia induction is here reported. METHODS: Sprague-Dawley rats (90-120 g) were administered with asiatic acid (10 mg/kg) 48 h before intraperitoneal infection with P. berghei. Parasitaemia induction and progression, food and water intake as well as weight were compared to 30 mg/kg chloroquine-treated and infected control rats during sub-chronic studies (21 days). RESULTS: Asiatic acid pre-infection administration preserved food and water intake as well as increase in percentage weight gain of infected animals. In pre-infection treated animals, the pre-patent period was extended to day 6 from 72 h. Asiatic acid suppressed parasitaemia while oral chloroquine (30 mg/kg) did not influence malaria induction. CONCLUSIONS: Per-oral, pre-infection, asiatic acid administration influenced parasitaemia patency and parasitaemia progression, food, water, and weight gain percentage. This may suggest possible chemoprophylaxis effects of asiatic acid in malaria.

Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats.

Maternal separation has been associated with development of anxiety-like behaviour and learning impairments in adult rats. This has been linked to changes in brain morphology observed after exposure to high levels of circulating glucocorticoids during the stress-hyporesponsive period (P4-P14). In the present study, adult rats that had been subjected to maternal separation (180 min/day for 14 days) during the stress-hyporesponsive period, received unilateral infusions of a small dose of 6-hydroxydopamine (6-OHDA, 5 microg/4 microl saline) into the medial forebrain bundle. The results showed that voluntary exercise had a neuroprotective effect in both non-stressed and maternally separated rats in that there was a decrease in forelimb akinesia (step test) and limb use asymmetry (cylinder test). Maternal separation increased forelimb akinesia and forelimb use asymmetry and reduced the beneficial effect of exercise on forelimb akinesia. It also reduced exploratory behaviour, consistent with anxiety-like behaviour normally associated with maternal separation. Exercise appeared to reduce dopamine neuron destruction in the lesioned substantia nigra when expressed as a percentage of the non-lesioned hemisphere. However, this appeared to be due to a compensatory decrease in completely stained tyrosine hydroxylase-positive neurons in the contralateral, non-lesioned substantia nigra. In agreement with reports that maternal separation increases the 6-OHDA-induced loss of dopamine terminals in the striatum, there was a small increase in dopamine neuron destruction when expressed as a percentage of the non-lesioned hemisphere but there was no difference in dopamine cell number, suggesting that exposure to maternal separation did not exacerbate dopamine cell loss.