Abdulaziz M. Aleisa

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: Molecular docking study

Novel derivatives of quinazoline (1-27) have been synthesized and tested for their antitumor activity against three tumor cell lines among these cell lines the human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. All tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC(50) range of 3.35-6.81 microg/ml. With regarding broad-spectrum activity compounds 5, 9, 15, 18 and 20 exploited potent antitumor against human liver cell line (HEPG2), human breast cell line (MCF-7) and human cervix cell line (HELA) with IC(50) range of 3.35-5.59 microg/ml. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

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.

Thymoquinone Attenuates Diethylnitrosamine Induction of Hepatic Carcinogenesis Through Antioxidant Signaling

Hepatocellular carcinoma accounts for about 80–90% of all liver cancer and is the fourth most common cause of cancer mortality. Although there are many strategies for the treatment of liver cancer, chemoprevention seems to be the best strategy for lowering the incidence of this disease. Therefore, this study has been initiated to investigate whether thymoquinone (TQ), Nigella sativa derived-compound with strong antioxidant properties, supplementation could prevent initiation of hepatocarcinogenesis-induced by diethylnitrosamine (DENA), a potent initiator and hepatocarcinogen, in rats. Male Wistar albino rats were divided into four groups. Rats of Group 1 received a single intraperitoneal (I.P.) injection of normal saline. Animals in Group 2 were given TQ (4 mg/kg/day) in drinking water for 7 consecutive days. Rats of Group 3 were injected with a single dose of DENA (200 mg/kg, I.P.). Animals in Group 4 were received TQ and DENA. DENA significantly increased alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) and decreased reduced glutathione (GSH), glutathione peroxidase (GSHPx), glutathione-s-transferase (GST) and catalase (CAT) activity in liver tissues. Moreover, DENA decreased gene expression of GSHPx, GST and CAT and caused severe histopathological lesions in liver tissue. Interestingly, TQ supplementation completely reversed the biochemical and histopathological changes induced by DENA to the control values. In conclusion, data from this study suggest that: (1) decreased mRNA expression of GSHPx, CAT and GST during DENA-induced initiation of hepatic carcinogenesis, (2) TQ supplementation prevents the development of DENA-induced initiation of liver cancer by decreasing oxidative stress and preserving both the activity and mRNA expression of antioxidant enzymes.

Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF.

Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimers disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism.

Electrophysiological investigation of basal synaptic transmission and synaptic plasticity in the CA1 region of the hippocampus was carried out in anesthetized obese Zucker rats (OZR). Comparison of the input/output curves of basal field excitatory postsynaptic potential indicates that these are similar in both the OZR and its lean counterpart suggesting that basal synaptic transmission is intact in the OZR. However, high frequency stimulation evokes long-term potentiation (LTP) in the lean rat but not in the OZR. Since post-tetanic potentiation and paired pulse facilitation, forms of short-term potentiation of presynaptic origin, are also severely impaired in the OZR, the results imply that impairment of CA1 hippocampal LTP in these obese rats may be due, in part, to impaired presynaptic function. The results emphasize the potential deleterious effect of obesity on learning and memory functions of the CNS.

Caffeine prevents sleep loss-induced deficits in long-term potentiation and related signaling molecules in the dentate gyrus

We have previously reported that caffeine prevented sleep deprivation‐induced impairment of long‐term potentiation (LTP) of area CA1 as well as hippocampus‐dependent learning and memory performance in the radial arm water maze. In this report we examined the impact of long‐term (4‐week) caffeine consumption (0.3 g/L in drinking water) on synaptic plasticity ( Alhaider et al., 2010 ) deficit in the dentate gyrus (DG) area of acutely sleep‐deprived rats. The sleep deprivation and caffeine/sleep deprivation groups were sleep‐deprived for 24 h by using the columns‐in‐water technique. We tested the effect of caffeine and/or sleep deprivation on LTP and measured the basal levels as well as stimulated levels of LTP‐related molecules in the DG. The results showed that chronic caffeine administration prevented the impairment of early‐phase LTP (E‐LTP) in the DG of sleep‐deprived rats. Additionally, chronic caffeine treatment prevented the sleep deprivation‐associated decreases in the basal levels of the phosphorylated calcium/calmodulin‐dependent protein kinase II (P‐CaMKII) and brain derived neurotrophic factor (BDNF) as well as in the stimulated levels of P‐CaMKII in the DG area. The results suggest that chronic use of caffeine prevented anomalous changes in the basal levels of P‐CaMKII and BDNF associated with sleep deprivation and as a result contributes to the revival of LTP in the DG region.

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.

Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia

Long-term potentiation in sympathetic ganglia (gLTP) is an activity-dependent unique form of synaptic plasticity in that it is serotonin-dependent and can be completely inhibited by 5-HT3 receptor antagonists. Long lasting enhancement of the basal tone of ganglionic transmission seen with gLTP results in a sustained increase in peripheral resistance that leads to elevated blood pressure. We examined the possibility that, in sympathetic ganglia, stress-induced gLTP may be responsible for the expression of stress hypertension. Chronic treatment of male and female Wistar rats with a 5-HT3 receptor antagonist, tropisetron (ICS; 5 mg/kg/day) or ondansetron (0.5 mg/kg/day), prevented or reversed psychosocial stress-induced increases in blood pressure in stressed rats with no significant effect on blood pressure of unstressed control rats. Pharmacological and electrophysiological evidence that supports the presence of gLTP in ganglia isolated from stressed hypertensive rats includes inhibition of basal synaptic transmission by 5-HT3 antagonists, failure to induce gLTP with repetitive stimulation indicating occlusion of gLTP due to saturation and a left hand shift of the input/output curve. We suggest that a sustained stress-induced increase in central sympathetic efferent impulses to ganglia may provide the repeated high frequency presynaptic activity required to induce gLTP in sympathetic ganglia, thereby enhancing sympathetic tone to blood vessels resulting in hypertension.

Nicotine Reverses Adult-Onset Hypothyroidism-Induced Impairment of Learning and Memory: Behavioral and Electrophysiological Studies

Nicotine alleviates cognitive impairment associated with a variety of health conditions. We examined the effect of chronic nicotine treatment on adult‐onset hypothyroidism‐induced impairment of learning and memory in rats. Hypothyroidism was induced by surgical removal of thyroid glands (thyroidectomy). One month later, chronic nicotine treatment (1 mg/kg sc, twice/day) was instituted for 4–6 weeks. Test of hippocampus‐dependent spatial learning and memory in the radial arm water maze showed that hypothyroidism impaired learning as well as short‐term and long‐term memory retention. Chronic nicotine treatment reversed the hypothyroidism‐induced learning and memory impairment. In normal rats, chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anesthetized hypothyroid rats showed severe reduction of both early‐phase and late‐phase long‐term potentiation (LTP) magnitude, which was reversed in nicotine‐treated hypothyroid rats. These results show that chronic nicotine treatment prevents hypothyroidism‐induced impairment of spatial cognition and LTP.