Day 2 :
Keynote Forum
Philip Liu
Harvard Medical School, USA
Keynote: Interaction of microRNA on HDAC5 expression in Neural Remodeling and Amphetamineinduced Sensitization
Time : 09:00-09:40
Biography:
Philip K. Liu, PhD
Associate Professor of Radiology, Harvard Medical School and Associate Biologist of Mass General Hospital. Director of Gene Transcript Targeting and Imaging, AA Martinos Center for Biomedical Imaging. CNY 149 (2301) Thirteenth Street,Charlestown, MA 02129.
Abstract:
Background & Aim: Histone deacetylase (HDAC) activities modify chromatin structure and play a role in learning and memory during developmental processes. Studies of adult mice suggest HDACs are involved in neural network remodeling in brain repair, but its function in drug addiction is less understood. We aimed to examine in vivo HDAC5 expression in a preclinical model of amphetamine-induced sensitization (AIS) of behavior. We generated specific contrast agents to measure HDAC5 levels by in vivo molecular contrast-enhanced (MCE) magnetic resonance imaging (MRI) in amphetamine-naïve mice as well as in mice with AIS. To validate the MRI results, we used ex vivo methods including in situ hybridization, RT-PCR, immunohistochemistry and transmission electron microscopy.
Methods: We compared the expression of HDAC5 mRNA in an acute exposure paradigm (A1) and in a chronic-abstinence-challenge paradigm (A7WA). Control groups for each of these exposure paradigms were given saline. To delineate how HDAC5 expression was related to AIS, we compared the expression of HDAC5 mRNA at sequences where miR-2861 is known to bind (miD2861). We synthesized and labeled phosphorothioated oligonucleic acids (sODN) of hdac5AS2 or miD2861 linked to SPION (superparamagnetic iron oxide nanoparticles), and generated HDAC5-specific contrast agents (30+20 nm, diameter) for MCE MRI; the same sequences were used for primers for TaqMan® analysis (RT-qPCR) in ex vivo validation. In addition, we used subtraction R2* maps to identify regional HDAC5 expression.
Results: Chronic exposure to amphetamine reduced HDAC5 expression and induced behavioral sensitization immediately after amphetamine. We designed HDAC5 mRNA targeting nanoparticles (miD2861) based on miR2861 binding to HDAC5. We identified regional elevation of HDAC5 expression and progenitor cells in the lateral septum in living mouse brain using MCE MRI; miD2681 targets HDAC5 mRNA in vivo using MCE MRI with precision similar to that of RT-PCR; excessive miD2861 shorten the AIS from 40 minutes to 15 minutes after amphetamine in acute exposure; ex vivo validation methods confirm that EDNs do not accumulate in any particular cell type.
Summary & Conclusion: The precise delivery of miD2861 may serve as a vehicle for monitoring network remodeling with target specificity and signal sensitivity after drug exposure that identifies brain repair processes in adult animals.
Keynote Forum
Hong Ni
National Natural Science Foundation of China, China
Keynote: Zinc/cPLA2 associated-mitophagy and CaMK II signaling contributed to the neuroprotective effects of chronic leptin treatment following neonatal seizures
Time : 11:20-12:00
Biography:
Ni Hong is a Medicine Doctor, completed his PhD in Medicine. Currently, he is the Director in Department of Neurology at Children’s Hospital of Soochow University and member of the Chinese Society of Microcirculation Council. His research focuses on “The children neurological rehabilitation, cerebral palsy and epilepsy”.
Abstract:
The peptide hormone leptin is an important neuromodulator for brain energy homeostasis which has recently received considerable attention in neurodegenerative diseases. The aim of the present study was to evaluate whether chronic leptin treatment immediately after flurothyl-induced recurrent neonatal seizures would exert neuroprotective effects on neurobehavior, cognition and hippocampal mossy fiber sprouting, and whether this effects were achieved by the pathway of Zinc/cPLA2 associated-mitophagy and CaMK II signaling. 40 Sprague-Dawley rats (postnatal day six, P6) were randomly assigned to recurrent seizures group and control group. On P13, they were further randomly divided into the seizure group without leptin (RS), seizure plus leptin (RS+Leptin, 2 mg/kg/day, consecutive ten days), the control group without leptin (control), and the control plus leptin (leptin, 2 mg/kg/day, consecutive 10 days). Neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex and open field test) were observed from P23 to P30. Morris water maze test was performed during P27-P32. Mossy fiber sprouting and protein levels in hippocampus were detected subsequently by Timm staining and western blot method, respectively. Flurothyl-induced seizures (RS group) significantly down-regulated mitophagy marker PINK/Drp1, pPLA2 and CaMK II alpha, meanwhile up-regulated zinc transporter ZnT1/ZIP7, lipid membrane injury-related cPLA2, autophagy marker beclin-1/bcl2, LC3II/LC3I, and its execution molecule cathepsin-E, which are in parallel with hippocampal aberrant mossy fiber sprouting and neurobehavioral and cognitive deficits. However, these changes were restored by chronic leptin treatment (RS+leptin group). The results imply that a zinc/lipid metabolism-associated mitophagy and CaMK II signaling is involved in the aberrant hippocampal mossy fiber sprouting and neurobehavioral deficits following neonatal seizures, which might be a potential target of leptin for the treatment of neonatal seizure-induced long-term brain damage.
Keynote Forum
Mootaz Salman
Sheffield Hallam University, UK
Keynote: Validation of the aquaporin role as a novel drug targets in therapeutic mannitol action and resistance in cerebral oedema and stroke
Time : 12:00-12:40
Biography:
Mootaz Salman is a pharmacist and researcher PhD student at the Biomolecular Sciences Research Centre (BMRC) at Sheffield Hallam University, working with Prof. Nicola Woodroofe and Dr. Matthew Conner’s research group and a member of the multi-institute Aquaporin research collaboration. His research interest focus on the identification of new drug targets for brain oedema and epilepsy through his work on the special water channels called “Aquaporins”. Mootaz graduated with Outstanding Distinction in his MSc winning the Sheffield Hallam University prize for the most scientific contribution and ranked 1st in year. His PhD research requires the skilled use of numerous techniques ranging from standard biochemical and molecular biology to cutting edge micro-array and laser confocal microscopy. Mootaz is an international ambassador at Sheffield Hallam University, ambassador for British Society of Experimental Biology (SEB); and STEM ambassador since 2014. He has given four invited oral presentations and talks at major international conferences in Canada, Netherlands, Romania and Japan along with three talks at a national level. He is also an active member in a number of scientific societies nationally and internationally including USA, Canada and Japan. He has been selected to be an abstract reviewer at two major international conferences; Brain 2015 in Canada and also for the upcoming Brain 2017 in Berlin, along with being an abstract reviewer and a member of poster judgement panel during the North of England Postgraduate Conference (NEPG) which is the UK's largest annual postgraduate conference for medical biosciences. Mootaz has successfully participated in organising a number of national and international high profile conferences and also he has been selected to chair scientific sessions at two national events
Abstract:
In humans there are 13 established members of the aquaporin (AQP) membrane protein water channels (AQP0-12) with a further two possible members recently discovered (AQP 13 & 14). AQPs are distributed throughout a wide range of tissues and involved in many physiologies; they have been shown to play a role in diverse disorders and pathologies1. Consequently, AQPs have been highlighted as key drug targets2. AQPs mediate water influx during cerebral oedema following ischemia as a result of traumatic brain injury or stroke. A number of AQPs have been shown to be expressed in the brain with AQP1 and 4 the most abundant. This project aimed to identify and study the molecular tools that could manipulate the translocation of brain AQPs as promising drug targets and also understanding the mechanisms of action/resistance for mannitol; which is considered to be a mainstay and gold standard to treat brain edema in order improve its therapeutic effectiveness.
Microarray on primary rat astrocytes has been used to investigate the possible mechanisms involved in the process of oedema under hypoxic and/or normoxic conditions. qRT-PCR was used to confirm the transcriptional capacity of the genes of interest from the microarray data. Potential key proteins within suggested mechanistic pathways were identified through analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID).
- Neuropharmacology and Neurogenesis
Location: Meeting Hall 4 & 5
Session Introduction
Ramel Carlos
The Neurology Clinic, USA
Title: Obstructive Sleep Apnea in Dementia
Time : 14:00-14:20
Biography:
Ramel A Carlos is a Board Certified Neurologist. He is currently working at Neurology Clinic in Tamuning, Guam. He completed his Residency and fellowship training at Wake Forest University, Winston-Salem, North Carolina.
Abstract:
Emerging evidence suggested a link between Obstructive Sleep Apnea (OSA) and cognitive decline, including dementia. The severity of cognitive impairment has been reported to be directly correlated with the degree of OSA. Neurodegenerative changes and vascular diseases are significant comorbidities on these patients. We report the occurrence of OSA in patients with dementia in the Island of Guam and to correlate the severity of OSA with the results of the neuropsychological testing and neuroimaging studies. We also report the prevalence of comorbid vascular diseases in these patients. A retrospective analysis of medical records of patients evaluated at Neurology Clinic with the diagnosis of OSA and dementia from August 2006 to June 2016 was conducted. There were 359 patients with dementia and 17% have been diagnosed with OSA. Among patients with OSA, 45% have moderate to severe OSA with moderate degree of cerebral atrophy on the neuroimaging studies and 17% have mild OSA with mild degree of cerebral atrophy. 17% of patients with moderate to severe OSA have moderate impairment on global cognitive scores and 17% with mild OSA have mild impairment on global cognitive scores. 25% of patients with moderate to severe OSA have stroke and 17% have leukoaraiosis in the neuroimaging studies. The prevalence of vascular diseases on patients with moderate to severe dementia showed that 75%, 58%, 66% and 33% of patients have hypertension, diabetes mellitus, hyperlipidemia and heart diseases, respectively, Wherein patients with mild dementia, hypertension, diabetes mellitus, hyperlipidemia and heart diseases were identified on 70%, 54%, 60% and 30% of patients, respectively. Conclusion: OSA is a common sleep disturbance in patients with dementia. The severity of OSA correlates closely with the degree of cerebral atrophy and global cognitive scores. Various comorbid vascular diseases are frequently encountered in patients with OSA and dementia.
Boon Chuan Low
National University of Singapore, Singapore
Title: Vesicular trafficking of cholinergic machinery in acetylcholine signaling requires scaffold protein BNIP-H working in concert with kinesin motor and Rab GTPases
Time : 14:20-14:40
Biography:
Boon Chuan Low is a Principal Investigator at Mechanobiology Institute and Department of Biological Sciences, National University of Singapore. His research work focuses on “Defining cellular and molecular mechanisms underlying neuronal differentiation and cancer metastasis”. His discovery on the BCH domain as a versatile protein scaffold has led to our better understanding of the intricate spatiotemporal regulation of GTPases, kinases and metabolic signaling in cell morphogenesis, cell motility, cell growth and differentiation. His work also extends to BCH and other scaffold proteins that can integrate both biochemical and mechanical signals in cell-cell and cell-matrix interaction, leading to tissue organization and organogenesis.
Abstract:
The neurotransmitter acetylcholine (ACh) is essential for neuron development, memory, learning and motor movement. It is synthesized from choline and acetyl-CoA by choline acetyl transferase (ChAT). ATP citrate lyase (ACL) is a key metabolic enzyme that produces the acetyl-CoA for this process. However, the precise spatial disposition of this cholinergic machinery for both morphogenesis and neurotransmission remain largely unknown. Mutations in the ATCAY/Atcay gene, which encodes a BCH domain containing BNIP-H (also known as caytaxin), lead to ataxia and mental retardation in humans (cayman ataxia), as well as ataxia and dystonia in several rodent models. Recently, we used molecular genetics, biochemical and imaging methods and revealed that BNIP-H recruits the cholinergic machinery to neurite terminal to regulate cholinergic signaling. BNIP-H links kinesin-1 (KLC1) motor protein to ACL and transports ACL towards neurite terminal. Therefore, the BNIP-H/ACL complex synergistically recruits ChAT, leading to enhanced secretion of ACh. ACh then activates MAPK/ERK via muscarinic receptors to promote neuritogenesis. In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented. Significantly, Bnip-h knockdown in zebrafish causes axon defect of motor neuron through impaired cholinergic pathway, leading to motor disorder. Here, we further show that BNIP-H specifically engages Rab11 GTPases and a component of the actin-based exocyst complex to regulate its dynamic disposition and neurologic function. In conclusion, BNIP-H promotes cholinergic signaling by trafficking ACL to neurite end, where ChAT is subsequently recruited to regulate the local production of ACh. Our results provide the first molecular evidence that precise spatial regulation of the cholinergic machinery is crucial in neuronal differentiation and neurotransmission, the significance of which will be further discussed.
Seyyedeh Elaheh Mousavi
Tehran University of Medical Sciences, Iran
Title: Minocycline Attenuates Depressive - Like Behaviour Induced by Rat Model of Testicular Torsion: Involvement of Nitric Oxide Pathway
Time : 14:40-15:00
Biography:
Seyyedeh Elaheh Mousavi is an Assistant Professor of Pharmacology at Tehran Medical Science University. He has worked in different fields of Pharmacology in various in vivo and in vitro models. Currently, he has published more than 10 articles in the renowned journals of pharmacology.
Abstract:
Testicular torsion/detorsion (T/D) can induce depression in pre- and post-pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive-like behavior, as well as antidepressant-like activity of minocycline and possible involvement of nitric oxide (NO)/cyclic GMP pathway in this paradigm in male rats undergoing testicular T/D. Unilateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with Nx-nitro-L-arginine methyl ester (L-NAME), non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), specific inducible NOS inhibitor; L-arginine, an NO precursor; and selective PDE5I, sildenafil. After assessment of locomotor activity in open-field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease in plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D-operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant-like effect in the operated rats in the FST (p<0.001). Furthermore, combination of sub-effective doses of minocycline (80 mg/kg) and either L-NAME (10 mg/kg) or AG (50 mg/kg) demonstrated a significant robust antidepressant-like activity in T/D group (p<0.01). Consequently, NO/cGMP pathway was involved in testicular T/D-induced depressive-like behavior and antidepressant-like activity of minocycline in the animal model. Moreover, a contribution was observed between either decreased testosterone or elevated serum nitrite levels and depressive-like behavior following testicular T/D.
Azam Bakhtiarian
Tehran University of Medical Sciences, Iran
Title: The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels
Time : 15:00-15:20
Biography:
Azam Bakhtiaran has her expertise in Pharmacology. Her main research focus is on “Characterizing effect of different drugs on both in vitro and in vivo models. She has completed her PhD at University of California in Irvine and she is currently an Associate Professor of Pharmacology at Tehran University of Medical Sciences
Abstract:
Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABAA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5 mg/kg). Nitrazepam at dose of 0.5 mg/kg significantly decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05 mg/kg) with glibenclamide in TST (1 mg/kg) and in FST (0.3, 1 mg/kg) also showed antidepressant-like response. Beside, cromakalim (0.1 mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5 mg/kg) in both FST and TST, while cromakalim and glibenclamide alone could not change the immobility time compared to control group (P40.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1 mg/kg could increase the activity of the animal’s head-dipping and boost the curiosity and exploration behavior of mice. The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in both FST and TST.
Farahnaz Jazaerijooneghani
Tehran University of Medical Sciences, Iran
Title: Evaluation of chronic losartan treatment effect on cardiac chronotropic dysfunction in biliary cirrhotic rats
Time : 15:20-15:40
Biography:
Farahnaz Jazaerijooneghani has completed his MD and PhD at Tehran University of Medical Sciences. She has been Assistant Professors at Tehran University of Medical Sciences, Pharmacology department since 2013. She has published more than 10 papers in reputed journals and presented posters in EASL Congress (Europe) and Pharma Nutrition Congress in Philadelphia. She has supervised and advised more than 10 medical students, masters and PhD students.
Abstract:
Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction which is known as cirrhotic cardiomyopathy. Cardiac responsiveness to adrenergic stimulation is impaired in cirrhosis. Moreover, there is vagal nerve dysfunction which is related to neuromodulatory dysfunction of the angiotensin II in the cirrhosis. This study was aimed to explore the hypothesis that administration of losartan-angiotensin II receptor antagonist- increases cardiac chronotropic response to isoproterenol in cirrhotic rats; and if so, whether this is associated with altered cardiac TGF-β receptor expression. Cirrhosis was induced by surgical ligation of the bile duct (BDL) in male Wister rats. Half of the BDL-group and control group were treated with losartan for four weeks. Four weeks after bile duct ligation or sham surgery the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was assessed using standard organ bath. Pathological assessment was done on the atria. Moreover, the expression of TGF-β was assessed the atria using quantitative RT-PCR. Bile duct ligation could induce a significant hypo-responsiveness to adrenergic stimulation. In cirrhotic rats, the chronotropic responses increased after chronic treatment with losartan but it was not significant. Pathological study showed that losartan decreases fibrosis in atria in losartan treated cirrhotic group. TGF-β expression is markedly increased in cirrhotic rats which are significantly decreased in atria following administration of losartan. These results might be considered as angiotensin II role in cirrhotic cardiomyopathy but further studies are required to elaborate the mechanism as well as possible advantage of losartan. We conclude that cirrhosis in rats is associated with altered expression of TGF-β in atrium which losartan can ameliorate it.