Sodium butyrate enhances fear extinction and rescues hippocampal acetylcholinesterase activity in a rat model of posttraumatic stress disorder.

It is believed that impaired extinction of fear memories is an underlying cause for the development of posttraumatic stress disorder (PTSD). Histone deacetylases (HDAC) are enzymes that modulate extinction by changing the chromatin structure and altering protein synthesis in the brain. Studies show that stress modifies both HDAC activity and cerebral cholinergic neurotransmission. The present work aims to evaluate the effect of sodium butyrate (NaBu), an HDAC inhibitor, on behavioral markers of extinction and biochemical changes in HDAC and acetylcholinesterase activity in the hippocampus. NaBu was administered for 7 days in a group of rats that were exposed to single prolonged stress (SPS), as a model for PTSD. Contextual fear conditioning was performed on the 8th day, and fear extinction was measured in the next 4 consecutive days. Other behavioral tests to measure anxiety, locomotor activity and working memory were performed for further interpretation of the results. Hippocampal acetylcholinesterase and HDAC activity were also measured through biochemical tests. Behavioral results showed that treatment with NaBu can reverse the SPS-induced extinction deficits. Biochemical data indicated that while SPS induced overactivity in hippocampal HDAC, it decreased acetylcholinesterase activity in the region. Both effects were reversed after NaBu treatment. It seems that at least part of extinction deficiency in SPS exposed rats is related to hypoacetylation of acetylcholinesterase in the hippocampus. Preemptive therapy with an HDAC inhibitor reverses this process and is worth further evaluation as a possible therapeutic approach in PTSD.

Astaxanthin engages the l-arginine/NO/cGMP/KATP channel signaling pathway toward antinociceptive effects.

One of the main functions of the sensory system in our body is to maintain somatosensory homeostasis. Recent reports have led to a significant advance in our understanding of pain signaling mechanisms; however, the exact mechanisms of pain transmission have remained unclear. There is an urgent need to reveal the precise signaling mediators of pain to provide alternative therapeutic agents with more efficacy and fewer side effects. Accordingly, although the anti-inflammatory, antioxidative and anti-neuropathic effects of astaxanthin (AST) have been previously highlighted, its peripheral antinociceptive mechanisms are not fully understood. In this line, considering the engagement of l-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) signaling pathway in the antinociceptive responses, the present study evaluated its associated role in the antinociceptive activity of AST. Male mice were intraperitoneally (i.p.) injected with l-arginine (100 mg/kg), SNAP (1 mg/kg), L-NAME (30 mg/kg), sildenafil (5 mg/kg), and glibenclamide (10 mg/kg) alone and prior to the most effective dose of AST. Following AST administration, intraplantarly (i.pl) injection of formalin was done, and pain responses were evaluated in mice during the primary (acute) and secondary (inflammatory) phases of formalin test. The results highlighted that 10 mg/kg i.p. dose of AST showed the greatest antinociceptive effect. Besides, while L-NAME and glibenclamide reduced the antinociceptive effect of AST, it was significantly increased by l-arginine, SNAP and sildenafil during both the primary and secondary phases of formalin test. These data suggest that the antinociceptive activity of AST is passing through the l-arginine/NO/cGMP/KATP pathway.

Intra-prefrontal cyclosporine potentiates ketamine-induced fear extinction in rats.

Several brain regions, including the medial prefrontal cortex (mPFC), are important in the process of fear extinction learning. Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, which is shown to play a role in extinction modulation. Ketamine and calcineurin (CN), an intracellular protein phosphatase, have several common targets in the cells. Therefore, in the present study, our aim is to investigate the possible role of calcineurin in the mPFC on the enhancing effects of ketamine in fear extinction. First, different doses of a CN inhibitor, cyclosporine-A (CsA), were micro-injected into the infralimbic (IL) region of the mPFC prior to extinction training in a classical conditioning model in rats. Next, sub-effective doses of CsA (Intra-mPFC) and ketamine (i.p.) were co-administered in another cohort of rats to find their possible interactions. Enzymatic activity of calcineurin was measured in the IL-mPFC following drug administration. We used the elevated plus-maze (EPM) and open field (OF) test for further behavioral assessments. The results showed that CsA can enhance the extinction of conditioned fear and inhibit the enzyme CN at a dose of 20 nM. The combination of sub-effective doses of CsA (5 nM) and ketamine (10 mg/kg) could again enhance the extinction of fear and reduce CN activity in the region. Our results propose that inhibition of CN in the IL-mPFC is involved in the extinction of fear and ketamine enhancement of extinction is probably mediated by reducing CN activity in this part of the brain.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1ß diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Synthesis, docking and acetylcholinesterase inhibitory assessment of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives with potential anti-Alzheimer effects.

BACKGROUND: Alzheimer's disease (AD) as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh) concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE) inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer's disease. RESULTS: Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 µM) compared to donepezil (IC50 = 0.14 ± 0.03 µM). The results of the enzyme inhibition test (Ellman test) showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta) afforded a favorable potency (IC50 = 5.5 ± 0.7 µM). Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a. CONCLUSIONS: Synthesized compounds 4a-4l could be proposed as potential anticholinesterase agents.

Sex differences in acetylcholinesterase modulation during spatial and fear memory extinction in the amygdala; an animal study in the single prolonged stress model of PTSD.

Background and purpose: Men and women show different reactions to trauma and that is believed to be the reason behind the higher prevalence of post-traumatic stress disorder (PTSD) in women. Cholinergic signaling has long been known to be involved in the processing of fear-related information and the amygdala is a critical center for fear modulation. The main goal of the current research was to find (a) whether trauma results in different learning/extinction of fear or spatial-related information among male and female rats and (b) if trauma is associated with different acetylcholinesterase (AchE) activity in the amygdala. Experimental approach: We used single prolonged stress (SPS) as a PTSD model in this study. Normal and SPS animals of both sexes were tested in contextual and spatial tasks (learning and extinction). AchE activity in the amygdala was also measured during each process. Findings / Results: Results indicated that fear and spatial learning were impaired in SPS animals. SPS animals also had deficits in fear and spatial memory extinction and the effect was significantly higher in female- SPS than in the male-SPS group. In the enzymatic tests, AchE activity was increased during the fear extinction test and incremental changes were more significant in the female-SPS group. Conclusion and implications: Collectively, these findings provided evidence that sex differences in response to trauma were at least partly related to less fear extinction potential in female subjects. It also indicated that the extinction deficit was associated with reduced cholinergic activity in the amygdala of female animals.

Intra-mPFC injection of sodium butyrate promotes BDNF expression and ameliorates extinction recall impairment in an experimental paradigm of post-traumatic stress disorder.

Objectives: Therapeutic strategies that facilitate extinction are promising in the treatment of post-traumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) has a crucial role in neural plasticity, a process needed for the retention of fear extinction. In this study, we investigated the effects of local administration of a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu), on BDNF transcription and behavioral markers of extinction in the single prolonged stress (SPS) model of PTSD. Materials and Methods: NaBu was infused into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) of male rats. The freezing response was recorded as the criterion to assess fear strength on the day of extinction as well as 24 hr later in the retention test. Other behavioral tests were also measured to evaluate the anxiety level, locomotor activity, and working memory on the retention day. HDAC activity and BDNF mRNA expression were evaluated after the behavioral experiments. Results: NaBu facilitated the recall of fear extinction in SPS rats (P<0.0001). SPS rats had higher HDAC activity (P<0.0001) and lower BDNF expression (P<0.05) than non-SPS animals. Also, anxiety was higher in the SPS group (P<0.0001), but locomotor activity (P=0.61) and working memory (P=0.36) were not different between SPS and Non-SPS groups. Conclusion: Our findings provide evidence that the mechanism of action of NaBu in the improvement of extinction recall is mediated, in part, by enhancing histone acetylation and reviving BDNF expression in IL.

Dapsone reduced cuprizone-induced demyelination via targeting Nrf2 and IKB in C57BL/6 mice.

Objectives: Multiple Sclerosis (MS) is an inflammatory disorder wherein the myelin of nerve cells in the central nervous system is damaged. In the current study, we assessed the effect of Dapsone (DAP) on the improvement of behavioral dysfunction and preservation of myelin in the cuprizone (CPZ) induced demyelination model via targeting Nrf2 and IKB. Materials and Methods: MS was induced in C57BL/6 mice through diet supplementation of CPZ (0.2%) for 6 weeks, and DAP (12.5 mg/kg/day; IP) was administered for the last 2 weeks of treatment. Pole test and rotarod performance test, LFB and H&E staining, and Immunohistochemistry (IHC) staining of p-Nrf2 and p-IKB were performed. Furthermore, superoxide dismutase (SOD) and nitrite were measured. Results: DAP treatment prevented body loss induced by CPZ (P<0.001). Pole test showed that CPZ increased latency time to fall (P<0.0001) but the latency to reach the floor in the DAP-CPZ group was significantly shorter (P<0.0001). Rotarod performance test showed the effect of CPZ in reducing fall time in the CPZ group (P<0.0014); however, DAP significantly increased fall time (P=0.0012). In LFB staining, DAP reduced demyelination induced by CPZ. CPZ significantly decreased p-Nrf2 and elevated p-IKB levels compared with the control group (P<0.0001), but in DAP-treated groups markedly modified these changes (P<0.0001). CPZ increased the brain nitrite levels and reduced SOD activity, but in DAP-treated considerably reversed CPZ-induced changes. Conclusion: These data support the suggestion that the beneficial properties of DAP on the CPZ-induced demyelination are mediated by targeting Nrf2 and NF-kB pathways.

Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activities.

Background: Spinal cord injury (SCI) is one of the most debilitating disorders throughout the world, causing persistent sensory-motor dysfunction, with no effective treatment. Oxidative stress and inflammatory responses play key roles in the secondary phase of SCI. Naringenin (NAR) is a natural flavonoid with known anti-inflammatory and antioxidative properties. This study aims at evaluating the effects of intrathecal NAR administration on sensory-motor disability after SCI. Methods: Animals underwent a severe compression injury using an aneurysm clip. About 30 minutes after surgery, NAR was injected intrathecally at the doses of 5, 10, and 15 mM in 20 µL volumes. For the assessment of neuropathic pain and locomotor function, acetone drop, hot plate, inclined plane, and Basso, Beattie, Bresnahan tests were carried out weekly till day 28 post-SCI. Effects of NAR on matrix metalloproteinase (MMP)-2 and MMP-9 activity was appraised by gelatin zymography. Also, histopathological analyses and serum levels of glutathione (GSH), catalase and nitrite were measured in different groups. Results: NAR reduced neuropathic pain, improved locomotor function, and also attenuated SCI-induced weight loss weekly till day 28 post-SCI. Zymography analysis showed that NAR suppressed MMP-9 activity, whereas it increased that of MMP-2, indicating its anti-neuroinflammatory effects. Also, intrathecal NAR modified oxidative stress related markers GSH, catalase, and nitrite levels. Besides, the neuroprotective effect of NAR was corroborated through increased survival of sensory and motor neurons after SCI. Conclusions: These results suggest intrathecal NAR as a promising candidate for medical therapeutics for SCI-induced sensory and motor dysfunction.

In vivo blockade of 5HT3 receptors in the infralimbic medial prefrontal cortex enhances fear extinction in a rat model of PTSD.

OBJECTIVES: Treatments that reverse deficits in fear extinction are promising for the management of post-traumatic stress disorder (PTSD). 5-Hydroxytryptamine type 3 (5-HT3) receptor is involved involved in the extinction of fear memories. The present work aims to investigate the role of 5HT3 receptors in the infralimbic part of the medial prefrontal cortex (IL-mPFC) in extinction of conditioned fear in the single prolonged stress (SPS) model of PTSD in rats. MATERIALS AND METHODS: The effect of SPS administration was evaluated on the freezing behavior in contextual and cued fear conditioning models. After the behavioral tests, levels of 5HT3 transcription in IL-mPFC were also measured in the same animals using the real-time RT-PCR method. To evaluate the possible role of local 5HT3 receptors on fear extinction, conditioned freezing was evaluated in another cohort of animals that received local microinjections of ondansetron (a 5HT3 antagonist) and ondansetron plus a 5HT3 agonist (SR 57227A) after extinction sessions. RESULTS: Our findings showed that exposure to SPS increased the freezing response in both contextual and cued fear models. We also found that SPS is associated with increased expression of 5HT3 receptors in the IL-mPFC region. Ondansetron enhanced the fear of extinction in these animals and the enhancement was blocked by the 5HT3 agonist, SR 57227A. CONCLUSION: It seems that up-regulation of 5HT3 receptors in IL-mPFC is an important factor in the neurobiology of PTSD and blockade of these receptors could be considered a potential treatment for this condition.

Trifluoperazine reduces cuprizone-induced demyelination via targeting Nrf2 and IKB in mice.

Multiple sclerosis (MS) is one of the most common neurodegenerative diseases. In this disease, the immune system attacks oligodendrocyte cells and the myelin sheath of myelinated neurons in the central nervous system, causing their destruction. These conditions lead to impaired conduction of nerve impulses and are manifested by symptoms such as weakness, fatigue, visual and motor disorders. This study aimed to evaluate the ability of trifluoperazine (TF) to improve cuprizone-induced behavioral and histopathological changes in the prefrontal cortex of C57BL/6 male mice. Demyelination was induced by adding 0.2% cuprizone (CPZ) to the standard animal diet for 6 weeks. Three doses of TF (0.5, 1 and 2 mg/kg/day; i.p.) were given once daily for the last 2 weeks of treatment. Treatment with CPZ induced a weight loss during 6 weeks of treatment compared to the control group, which was reversed by the administration of TF. Behavioral tests (pole test and rotarod performance test) showed a decrease in motor coordination and balance in the group treated with CPZ (P < 0.01). Treatment with TF during the last two weeks was able to improve these motor deficiencies. Histopathological examination also evidenced an increase in demyelination in the CPZ group, which was improved by TF administration. In addition, CPZ intake significantly decreased the cerebral cortex levels of p-Nrf2 (P < 0.001) and increased the levels of p-IKB (P < 0.001) and, these changes were normalized in the TF groups. TF administration also reversed the increased levels of nitrite and the reduced activity of the antioxidant enzyme superoxide dismutase associated with CPZ exposure. TF can to reduce the harmful effects of CPZ by reducing the demyelination and modulating the Nrf2 and NF-kB signaling pathways.

Effects of HDAC inhibitors on spatial memory and memory extinction in SPS-induced PTSD rats.

BACKGROUND AND PURPOSE: Neurobiological changes in memory processes seem to play a role in the pathophysiology of post-traumatic stress disorder (PTSD). Memory itself is influenced by PTSD, too. Histone deacetylase inhibitors (HDAIs) have shown promising results in the extinction of fear-related memories in animals and hence they seem to be important for the treatment of PTSD. Data are scarce about the effect of HDAIs in spatial memory formation/extinction in PTSD models. The main goal of the present work is to find the effect of sodium butyrate (NaBu), as an HDAI, on spatial memory and spatial memory extinction in rats exposed to single prolonged stress procedure (SPS). EXPERIMENTAL APPROACH: Different doses of NaBu were administered subcutaneously for 7 days in different groups of rats after SPS procedure. Learning, memory, and extinction of memory were evaluated in the Morris water maze test of spatial memory in 6 consecutive days. FINDINGS / RESULTS: The results show that NaBu (0.5 mg/kg) alleviates impaired learning and memory in SPS rats. It also facilitates the extinction of newly formed memory in the animals. CONCLUSION AND IMPLICATIONS: Our data suggest that the administration of HDAIs after a traumatic experience can prevent the aversive effects of SPS on spatial memory. It also reinforces the notion that extinction of spatial memory involves the same or similar brain circuitry that is involved in the extinction of fear memories in PTSD patients.

Synthesis and evaluation of anticonvulsant activity of (Z)-4-(2-oxoindolin-3-ylideneamino)-N-phenylbenzamide derivatives in mice.

Due to resistance of some epileptic patients to the current medications and the general incidence of severe side effects of these drugs, development and discovery of novel antiepileptic drugs is crucial. Isatin-based derivatives are promising compounds as antiepileptic agents. In this study a new series of isatin-containing derivatives were synthesized via the imine formation between isatin and p-aminobenzoic acid. Subsequently, the obtained acidic compound was utilized to prepare the final amidic derivatives (4a-4l) through the reaction with various aniline derivatives. Then, their anti-seizure activity was investigated using maximal electroshock seizure (MES) as well as pentylenetetrazole (PTZ) models in mice. Neurotoxicity of target compounds was also determined by rotarod test. Tested isatin-based derivatives exhibited a favorable protection in both MES and PTZ procedures with high safety levels in neurotoxicity test. The introduced derivatives have demonstrated remarkable activity in mice and could be suggested as potential anticonvulsant lead compounds. All methoxylated derivatives (4j, 4k, 4l) showed a significant anti-seizure activity in MES model. Compounds 4j (2-OCH3) and 4l (4-OCH3) also demonstrated a potent anti-seizure activity against PTZ. Compound 4k (m-OCH3) did not induce protection towards PTZ-induced convulsion.

Synthesis and Biological Evaluation of N-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)benzamide Derivatives as Lipoxygenase Inhibitor with Potential Anticancer Activity.

In the recent years, the role of LOX enzymes in the origin of neoplastic diseases such as colorectal, skin, pancreatic and renal cancers has been confirmed. A new series of 1,3,4-thiadiazole derivatives bearing 2-pyridyl moiety was synthesized and the cytotoxicity of the members of this series was assessed using MTT protocol. Enzyme inhibitory activity of the prepared compounds was also tested against 15-lipoxygenase-1 as a novel target for the discovery of anticancer drugs. PC3, HT29 and SKNMC cell lines were utilized and the obtained results were compared with doxorubicin. Overall, nitro containing derivatives exerted a higher cytotoxic activity against PC3 cell line and methoxylated derivatives showed an acceptable activity against SKNMC cell line. Methoxylated derivatives were also the most potent enzyme inhibitors especially at position ortho of the phenyl residue.

2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives: Synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents.

OBJECTIVES: Alzheimer's disease (AD) as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE) inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs. MATERIALS AND METHODS: A new series of phthalimide derivatives (compounds 4a-4j) were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j) was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions. RESULTS: According to the obtained results, electron withdrawing groups (Cl, F) at position 3 and an electron donating group (methoxy) at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM) and 4i (p-Methoxy, IC50 = 20.3 nM) were the most active compounds in this series and exerted superior potency than donepezil (410 nM). Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase. CONCLUSION: Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.

Synthesis and Acetylcholinesterase Inhibitory Evaluation of 4-(1,3-Dioxoisoindolin-2-yl)-N-Phenyl Benzamide Derivatives as Potential Anti-Alzheimer Agents.

Alzheimerá¾½s disease is characterized by cognitive deficits, impaired long-term potentiation of learning and memory. A progressive reduction in cholinergic neurons in some areas of the brain such as cortex and hippocampus is related to the deficits in memory and cognitive function in Alzheimer's disease (AD). In the current project a new series of phthalimide derivatives were synthesized. Phthalic anhydride was reacted with 4-aminobenzoic acid in the presence of triethylamine under reflux condition. Then, the obtained acidic derivative was utilized for preparation of final compounds via an amidation reaction through a carbodiimde coupling reaction. Anti-acetylcholinesterase activity of synthesized derivatives was assessed by Ellmaná¾½s test. Compound 4g in this series exhibited the highest inhibitory potency (IC50 = 1.1 ± 0.25 µM) compared to donepezil (IC50 = 0.41 ± 0.12 µM) as reference drug.

Synthesis and evaluation of LOX inhibitory activity of 2-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N-phenylacetamide derivatives.

A family of structurally related LOX enzymes present in human cells which catalyse the metabolism of released arachidonic acid from phospholipids by inflammatory stimuli, to biologically active mediators. Mainly, expression of three types of LOXs occurs in cells, which catalyse the insertion of molecular oxygen into the molecule of arachidonic acid at carbon 5, 12, and 15. According to this chemical reaction, the LOXs are named 5-, 12-, and 15-LOX, amongst which, 15-LOX with isoforms 15-LOX-1 and 15-LOX-2 have critical role in neoplastic diseases. 15-LOX-1 is overexpressed in some neoplastic conditions. Hence, in this research, we focused on the synthesis of naphthalimide analogs as potential 15-LOX-1 inhibitors. Fortunately, the most of synthesized compounds demonstrated remarkable inhibitory potency towards 15-LOX-1 in nanomolar ranges. Naphthalimide derivatives could be suggested as potential LOX inhibitors with likely applications of anticancer activity.

Effects of long term administration of testosterone and estradiol on spatial memory in rats.

There are many discrepancies around the effect of sex hormones on spatial learning and memory in rodents. The aim of the present study was to investigate the effects of chronic administration of estradiol (ES) and testosterone (TES) on spatial memory in adult castrated male rats. Cholinesterase activity of the hippocampus in treated animals was also measured to seek if hormonal treatment can change the acetylcholinesterase (AChE) activity in this region. Six groups of castrated male rats received different doses of ES valerate (1, 4, 10 mg/kg, by subcutaneous, sc) and TES enanthate (10, 20, 40 mg/kg, sc) in weekly injection intervals for 6 weeks. Morris water maze (MWM) was used to assess the spatial reference memory of the rats. The specific activity of AChE in the hippocampus was also measured. The treatment duration and the dose quantity of ES had significant (P<0.001 and P=0.048, respectively) effect on the learning ability in the rats. For TES treated rats, treatment duration showed a significant effect (P<0.001) on learning performance of the rats. The activity of AChE compared to the control group was significantly increased in ES treated rats in a dose dependent manner and it was decreased in the group that received the highest dose of TES. Our results showed that chronic high dose of ES decreased the learning ability of male castrated rats in a reference memory version of MWM test. This can be explained by the decreased AChE activity in the hippocampus.

Phthalimide analogs as probable 15-lipoxygenase-1 inhibitors: synthesis, biological evaluation and docking studies.

BACKGROUND: Recent studies have been explained the role of lipoxygenases (LOX) in the origin of cancer. Among the lipoxygenases, the 5-LOX, 12-LOX and 15-LOX are more important in the cause of neoplastic disorders. In the present investigation, a new series of anticancer agents with 1,3,4-thiadiazole and phthalimide substructures were synthesized and their in vitro cytotoxicity was evaluated by MTT assay. Moreover, enzyme inhibitory potency was also assessed by enzymatic protocol towards 15-LOX-1. Molecular docking was performed to explore in silico binding mode of the target compounds. RESULTS: Tested compounds showed a better cytotoxic activity against HT29 cell line (colorectal cancer) in comparison with other cell lines (PC3: prostate carcinoma; SKNMC: neuroblastoma). Unfortunately, all of the tested derivatives rendered lower inhibitory potency than quercetin towards 15-LOX-1. Four hydrogen bonds were detected in docking studies for compound 4d as the most potent derivative in enzymatic assay. CONCLUSIONS: The biological results of reported compounds in this research were not so satisfactory. But, further structural modifications are necessary to improve the bioactivity of these derivatives.

Dinitrobenzene sulphonic acid-induced colitis impairs spatial recognition memory in mice: roles of N-methyl D-aspartate receptors and nitric oxide.

RATIONALE: Many peripheral diseases are associated with a decline in cognitive function. In this regard, there have been reports of patients with inflammatory bowel disease and an otherwise unexplained memory impairment. OBJECTIVES: We sought to assess the memory performance of mice with colitis. We also investigated the roles of N-methyl D-aspartate (NMDA) receptors and nitric oxide (NO) as possible mediators of colitis-induced amnesia. METHODS: To induce colitis, male NMRI mice were intrarectally injected with a solution containing dinitrobenzene sulfonic acid (DNBS; 4 mg in 100 µl) under anesthesia. Three days after intrarectal DNBS instillation, spatial recognition and associative memories were assessed by the Y-maze and passive avoidance tasks, respectively. The NMDA antagonists, MK-801 and memantine, and the inducible NO synthase (iNOS) inhibitor, aminoguanidine, were injected intraperitoneally 45 min before the Y-maze task. RESULTS: Induction of colitis by DNBS impaired spatial recognition memory in the Y-maze task but had no effect on step through latencies in the passive avoidance test. Colitis-induced amnesia was reversed by administering specific doses of MK-801 and memantine (30 µg/kg and 1 mg/kg, respectively) suggesting dysregulated NMDA receptor activation as an underlying mechanism. No effect was seen with lower and higher doses of these drugs, resulting in a bell-shaped dose response curve. Colitis-induced amnesia was also inhibited by aminoguanidine (50 mg/kg), implicating a role for iNOS activation and neuroinflammation in this phenomenon. CONCLUSION: DNBS-induced colitis impairs memory through NMDA receptor overstimulation and NO overproduction.