Karem H. Alzoubi

Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats

Both hypothyroidism and stress interfere with cognitive function in patients. This study examined the effect of hypothyroidism and stress on hippocampus-dependent learning and memory in rats using the novel radial arm water maze (RAWM), which measures spatial working memory. Hypothyroidism was accomplished by thyroidectomy and 2 weeks later a form of intruder stress was used as the chronic psychosocial stressor. After 4-6 weeks of stress, rats were trained to learn (during the acquisition phase; four trials) and then remember (during two memory test trials occurring 15 and 120 min after the acquisition phase) the within-day location of a hidden escape platform, which was in different arm every day. The number of errors (entry into arms other than the platform arm) was noted. Within-day learning of the platform location was largely unaffected by the experimental manipulations, indicating that rats in all groups were equally capable of finding the platform to escape from the water with similar numbers of errors (P > 0.005). The number of days a rat took to reach a criterion (DTC; a maximum of one error in three consecutive days) indicated that chronic stress or hypothyroidism, alone, resulted in a mild impairment of spatial memory, and the combination of chronic stress and hypothyroidism resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and hypothyroidism produced more deleterious effects on hippocampal function than either chronic stress or hypothyroidism alone.

Levothyroxin restores hypothyroidism-induced impairment of hippocampus-dependent learning and memory: Behavioral, electrophysiological, and molecular studies.

Hypothyroidism induces cognitive impairment in experimental animals and patients. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism‐induced learning and memory impairment. In this study, we investigated the effects of L‐thyroxin (thyroxin) treatment on hippocampus‐dependent learning and memory in thyroidectomized adult rats. In the radial arm water maze (RAWM) task, thyroxin treated thyroidectomized animals made significantly fewer errors than the untreated hypothyroid animals in Trial 3 of the acquisition phase, short‐term memory and long‐term memory tests. In addition, the number of errors made by the thyroxin treated thyroidectomized animals was not different from that of the control group. Furthermore, the days‐to‐criterion (DTC) values for thyroxin treated thyroidectomized animals were not different from those of the control group but significantly lower than those of the untreated hypothyroid animals. In anesthetized rats, extracellular recording from hippocampal area CA1 of hypothyroid rats shows that thyroxin treatment restores impaired Late‐phase long‐term potentiation (L‐LTP). Immunoblot analysis of signaling molecules, including cyclic‐AMP response element binding protein (CREB), mitogen‐activated protein kinases (MAPKp44/42; ERK1/2), in area CA1 revealed that thyroxin treatment reversed hypothyroidism‐induced reduction of signaling molecules essential for learning and memory, and L‐LTP. This study shows that thyroxin treatment reverses hypothyroidism‐induced impairment of hippocampus‐dependent cognition, and L‐LTP, probably by restoring the levels of signaling molecule important for these processes.

Chronic Psychosocial Stress Exacerbates Impairment of Cognition and Long-Term Potentiation in β-Amyloid Rat Model of Alzheimer's Disease

BACKGROUND Alzheimers disease (AD) is a degenerative disorder that leads to progressive cognitive decline. Alzheimers disease develops as a result of over-production and aggregation of beta-amyloid (Abeta) peptides in the brain. The reason for variation in the gravity of symptoms among AD patients is unknown and might result from patient-related factors including lifestyle. Individuals suffering from chronic stress are at an increased risk for developing AD. This study investigated the effect of chronic psychosocial stress in Abeta rat model of AD. METHODS Psychosocial stress was induced with a rat intruder model. The rat model of AD was induced by 14-day osmotic pump infusion of a mixture of 300 pmol/day Abeta(1-40)/Abeta(1-42). The effect of chronic stress on the severity of Abeta-induced spatial learning and memory impairment was tested by three approaches: behavioral testing in the radial arm water maze, in vivo electrophysiological recording in anesthetized rat, and immunoblot analysis to determine protein levels of learning- and memory-related molecules. RESULTS A marked impairment of learning and memory developed when stress was combined with Abeta, more so than that caused by Abeta alone. Additionally, there was a significantly greater impairment of early-phase long-term potentiation (E-LTP) in chronically stressed/Abeta-treated rats than in either the stressed or Abeta-treated rats. This might be a manifestation of the reduction in protein levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and the abnormal increase in calcineurin levels. CONCLUSIONS Chronic stress significantly intensified Abeta-induced deficits of short-term memory and E-LTP by a mechanism involving decreased CaMKII activation along with increased calcineurin levels.

The neuroprotective effect of vitamin E on chronic sleep deprivation-induced memory impairment: The role of oxidative stress

Sleep deprivation induces oxidative stress and impairs learning and memory processes. Vitamin E, on the other hand, is a strong antioxidant that has neuroprotective effect on the brain. In this study, we examined the potential protective effect of chronic administration of vitamin E on chronic sleep deprivation-induced cognitive impairment. In addition, possible molecular targets for vitamin E effects on chronic sleep deprivation-induced cognitive impairment were determined. Sleep deprivation was induced in rats using modified multiple platform model. Vitamin E (100mg/kg) was administered to animals by oral gavage. Behavioral study was conducted to test the spatial learning and memory using the radial arm water maze (RAWM). In addition, the hippocampus was dissected out and antioxidant markers including glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) were assessed. The results of this project revealed that chronic sleep deprivation impaired both (short- and long-term) memories (P<0.05), while vitamin E treatment prevented such effect. Additionally, vitamin E normalized chronic sleep deprivation-induced reduction in the hippocampus GSH/GSSG ratio, and activity of catalase, SOD, and GPx. In conclusion, sleep deprivation induces memory impairment, and treatment with vitamin E prevented this impairment probably through its antioxidant action in the hippocampus.

Water pipe tobacco smoking among university students in Jordan

INTRODUCTION Although water pipe tobacco smoking is common in Lebanon and Syria, prevalence in neighboring Jordan is uncertain. The purposes of this study were (a) to assess the prevalence of water pipe tobacco smoking among university students in Jordan and (b) to determine associations between sociodemographic variables and water pipe tobacco smoking in this population. METHODS A trained interviewer administered a questionnaire among randomly selected students at four prominent universities in Jordan. The questionnaire assessed sociodemographic data, personal history of water pipe tobacco use, and attitudes regarding water pipe tobacco smoking. We used logistic regression to determine independent associations between sociodemographic and attitudinal factors and each of two dependent variables: ever use of water pipe and use at least monthly. RESULTS Of the 548 participants, 51.8% were male and mean age was 21.7 years. More than half (61.1%) had ever smoked tobacco from a water pipe, and use at least monthly was reported by 42.7%. Multivariable analyses controlling for all relevant factors demonstrated significant associations between ever use and only two sociodemographic factors: (a) gender (for women compared with men, odds ratio [OR] = 0.11, 95% CI = 0.07-0.17) and (b) income (for those earning 500-999 Jordanian dinar (JD) monthly vs. <250 JD monthly, OR = 2.37, 95% CI = 1.31-4.31). There were also significant associations between perception of harm and addictiveness and each outcome. DISCUSSION Water pipe tobacco smoking is highly prevalent in Jordan. Although use is associated with male gender and upper middle income levels, use is widespread across other sociodemographic variables. Continued surveillance and educational interventions emphasizing the harm and addictiveness of water pipe tobacco smoking may be valuable in Jordan.

Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies.

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 microg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCgamma basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.

Changes in spatial memory and BDNF expression to concurrent dietary restriction and voluntary exercise

Substantial data suggest that cognitive function can be influenced by many lifestyle activities associated with changes in energy metabolism such as exercise and diet. In the current study, we investigated the combined effects of voluntary exercise (access to running wheels) and dietary restriction (every other day fasting, EODF) on spatial memory formation and on the levels of brain‐derived neurotrophic factor (BDNF) in the hippocampus of Wistar male rats. Spatial learning and memory formation was assessed using the radial arm water maze (RAWM) paradigm, while BDNF protein was measured using ELISA test. Voluntary exercise and/or EODF were instituted for 6 weeks. Voluntary exercise alone significantly enhanced short‐term, intermediate‐term, and long‐term memory formation, and increased BDNF protein levels in the hippocampus. EODF enhanced mean running wheel activity by approximately twofold. However, EODF did not modulate the effects of exercise on memory formation and expression of BDNF. In addition, EODF alone had no effect on memory and BDNF protein in the hippocampus. In conclusion, results of this study indicate that exercise enhanced while EODF had neutral effect on both spatial memory formation and hippocampus BDNF levels.

Adverse effect of combination of chronic psychosocial stress and high fat diet on hippocampus-dependent memory in rats

The combined effects of high fat diet (HFD) and chronic stress on the hippocampus-dependent spatial learning and memory were studied in rats using the radial arm water maze (RAWM). Chronic psychosocial stress and/or HFD were simultaneously administered for 3 months to young adult male Wister rats. In the RAWM, rats were subjected to 12 learning trials as well as short-term and long-term memory tests. This procedure was applied on a daily basis until the animal reaches days to criterion (DTC) in the 12th learning trial and in memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Groups were compared based on the number of errors per trial or test as well as on the DTC. Chronic stress, HFD and chronic stress/HFD animal groups showed impaired learning as indicated by committing significantly (P<0.05) more errors than untreated control group in trials 6 through 9 of day 4. In memory tests, chronic stress, HFD and chronic stress/HFD groups showed significantly impaired performance compared to control group. Additionally, the stress/HFD was the only group that showed significantly impaired performance in memory tests on the 5th training day, suggesting more severe memory impairment in that group. Furthermore, DTC value for above groups indicated that chronic stress or HFD, alone, resulted in a mild impairment of spatial memory, but the combination of chronic stress and HFD resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and HFD produced more deleterious effects on hippocampal cognitive function than either chronic stress or HFD alone.

Acute Nicotine Treatment Prevents REM Sleep Deprivation-Induced Learning and Memory Impairment in Rat

Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long‐term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD‐induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg−1 s.c.) twice a day. In the radial arm water maze (RAWM) task, 24‐ or 48‐h SD significantly impaired learning and short‐term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24‐ and 48‐h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD‐induced impairment of learning and STM and prevented SD‐induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity.

Assessment of genotoxicity of waterpipe and cigarette smoking in lymphocytes using the sister-chromatid exchange assay: a comparative study.

Tobacco smoking is a major world health problem. Recently, waterpipe smoking has become more popular in many countries. Although the genotoxicity associated with cigarette smoking has been extensively investigated, studies evaluating such toxicity in waterpipe users are still lacking. In this study, we examined the genotoxicity of waterpipe smoking in lymphocytes compared with the genotoxicity of cigarette smoking. Genotoxicity was evaluated using the sister chromatid exchanges (SCEs) assay. Fifty waterpipe smokers and 18 healthy nonsmokers participated in this study. Additionally, 18 heavy cigarette smokers (CS) were recruited for comparison. The results show that waterpipe smoking and cigarette smoking significantly increase the frequencies of SCEs (P < 0.01) compared with those of nonsmokers, indicating the genotoxic effect of tobacco smoking. In addition, frequencies of SCEs were significantly higher among waterpipe smokers compared with CS (P < 0.01), indicating that waterpipe smoking is more genotoxic than cigarette smoking. Moreover, the frequency of SCEs increased with the extent of waterpipe use. In conclusion, waterpipe smoking is genotoxic to lymphocytes and the magnitude of its genotoxicity is higher than that induced by regular cigarette smoking. Environ. Mol. Mutagen., 2011.