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Pro-cognitive properties SUVN-D1108121, a potent and selective 5-HT4 receptor partial agonist
Poster Presentations: P1 Conclusions: Results of the present study suggest that piperine potentiates the protective effect of quercetin against chronic unpredictable stress induced memory dysfunction and oxidative stress in mice.
1. The Experimental design for the 28 day protocol of chronic unpredictable stress P1-263
PRO-COGNITIVE PROPERTIES SUVN-D1108121, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST
Ramakrishna Nirogi, Renny Abraham, Vijay Benade, Gopinadh Bhyrapuneni, Abinash Das, Arunkumar Manoharan, Ramu Yaramasu, Anil Shinde, Ramasastri Kambhampati, Adireddy Dwarampudi, Suven Life Sciences Ltd, Hyderabad, India. Background: Treatment of cognitive disorder is an unmet medical need in various disorders like Alzheimer’s disease (AD), schizophrenia and psychiatric related disorders. There is an urgent need of therapeutic agents in AD, which offers both symptomatic treatment and arrest of disease progression. It is known that 5-HT 4 receptor partial agonist has both symptomatic and disease modifying properties. It has been demonstrated that 5-HT 4 receptor partial agonist increases both acetylcholine and sAPP 6 levels in the brain. Currently we have evaluated a highly potent and selective 5-HT 4 receptor partial agonist, SUVN-D1108121 for its therapeutic potential Methods: SUVN-D1108121 was evaluated for episodic memory in the object recognition task (ORT) and for working memory in the radial arm maze. Rodent microdialysis was carried out in order to evaluate the acetylcholine modulation in the prefrontal cortex and hippocampus. Results: Rats that were treated with SUVN-D1108121, spent significantly more time with the novel object in comparison to the familiar object at the tested doses of 0.01-0.1 mg/kg, p.o. Scopolamine at a dose of 0.8 mg/kg reduced the choice accuracy in the radial maze and increased the total error. SUVN-D1108121 at doses of 0.1-1 mg/kg increased the choice accuracy and decreased in the total error. An inverted U dose response curve was obtained in the radial maze. An increase in the brain Ach levels of more than 200% was observed in the frontal cortex and in the hippocampus. Conclusions: SUVN-D1108121 was found to reverse the time induced and scopolamine induced memory deficit. The active dose of SUVN-D1108121 was as low as 0.01 mg/kg, p.o. in the ORT. Preliminary studies through brain microdialysis indicate that the reversal in memory deficit could be through an increase in the acetylcholine levels in brain regions responsible for learning and memory.
Background: Alzheimer’s disease is a neurodegenerative disorder with cognitive decline and synaptic loss. Increasing evidence indicates that factors such as oxidative stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer’s disease pathogenesis. Sesamol (5-hydroxy-1,3- benzodioxole or 3,4-methylenedioxyphenol) is a potent antioxidant and anti-inflammatory molecule. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer’s disease. The present study was designed to explore the effect of solid lipid nanoparticles (SLNs) of sesamol versus plain sesamol against intracerebroventricular streptozotocin-induced cognitive impairment in rats. Methods: Streptozotocin (3 mg/kg) was administered intracerebroventricularly to male Wistar rats twice on days 1 and 3. The rats were treated with sesamol plain and its SLN’s (4, 8 & 16 mg/kg, peroral) for 21 days starting from day 1 of STZ injection. After 21 days, animals were sacrificed and the brains were isolated for different biochemical and cytokines estimations. Results: Intracerebroventricular streptozotocin (ICV-STZ) produced significant cognitive deficits coupled with increased acetylcholinesterase activity, marked oxidative-nitrergic stress and elevated inflammatory cytokines. SLN’s of sesamol and plain sesamol (4, 8 and 16 mg/kg; peroral) supplementation significantly and dose-dependently improved cognitive impairment, reduced acetylcholinesterase activity, attenuated oxidative-nitrergic stress and inflammatory cytokines in ICV-STZ administered rats. SLNs of sesamol in the dose of 16 mg/kg were found to be most potent in improving all behavioral and biochemical indices and the efficacy was comparable to rivastigmine. Conclusions: Our findings demonstrate that solid lipid nanoparticles of sesamol could be used as potential therapeutic and brain targeting strategy to combat the global burden of Alzheimer’s disease.
P1-265
NEUROPROTECTIVE POTENTIAL OF SOLID LIPID NANOPARTICLES OF SESAMOL: POSSIBLE BRAIN TARGETING STRATEGY
Shubham Misra1, Anurag Kuhad2, Indupal Kaur2, Kanwaljit Chopra2, Panjab University, Chandigarh, India; 2Univ Inst Pharm Sci, Panjab University, Chandigarh, India.
1
EFFECTS OF RIVASTIGMINE IN THE TREATMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF ALZHEIMER’S DISEASE
Vladimir Janjic, Slavica Djukic Dejanovic, Branimir Radmanovic, Clinical Center Kragujevac, Kragujevac, Serbia. Background: Objective of this work is to investigate the effects of rivastigmine, a dual inhibitor of acetyl cholinesterase and butyrylcholinesterase, in decreasing and/or eliminating behavioral symptoms in patients with Alzheimer’s disease. Methods: Investigation included 37 patients with Alzheimer’s disease who have been treated with rivastigmine with gradual increase of doses to maximum average dose of 9,3 mg/d. Behavioral and psychological symptoms were assessed in patients by using the 12 item Neuropsychiatric inventory (NPI), at the beginning of the treatment, after 6 months and after 12 months. Results: Our results show statistically significant improvement of total score on NPI scale after 6 (P <0.05) and after 12 (P ¼ 0.001) months of following. After 6 months of treatment, significant improvement was noticed for following symptoms: irritability, anxiety, night restlessness and delusions, and after 12 months the improvement was noticed for symptoms: irritability, hallucinations, delusions, nigh restlessness and agitation. Conclusions: Based on obtained data we conclude that rivastigmine is an efficient medicine in treatment of behavioral and psychological symptoms of Alzheimer’s disease during the six-month and the one-year treatment.
P1-266 P1-264
P199
NEUROPROTECTIVE EFFECTS OF LITHIUM ON SCOPOLAMINEINDUCED AMNESIA THROUGH DECREASING QUINONE REDUCTASE 2 IN RATS
Yuanyuan Wu, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
1. The Experimental design for the 28 day protocol of chronic unpredictable stress P1-263
PRO-COGNITIVE PROPERTIES SUVN-D1108121, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST
Ramakrishna Nirogi, Renny Abraham, Vijay Benade, Gopinadh Bhyrapuneni, Abinash Das, Arunkumar Manoharan, Ramu Yaramasu, Anil Shinde, Ramasastri Kambhampati, Adireddy Dwarampudi, Suven Life Sciences Ltd, Hyderabad, India. Background: Treatment of cognitive disorder is an unmet medical need in various disorders like Alzheimer’s disease (AD), schizophrenia and psychiatric related disorders. There is an urgent need of therapeutic agents in AD, which offers both symptomatic treatment and arrest of disease progression. It is known that 5-HT 4 receptor partial agonist has both symptomatic and disease modifying properties. It has been demonstrated that 5-HT 4 receptor partial agonist increases both acetylcholine and sAPP 6 levels in the brain. Currently we have evaluated a highly potent and selective 5-HT 4 receptor partial agonist, SUVN-D1108121 for its therapeutic potential Methods: SUVN-D1108121 was evaluated for episodic memory in the object recognition task (ORT) and for working memory in the radial arm maze. Rodent microdialysis was carried out in order to evaluate the acetylcholine modulation in the prefrontal cortex and hippocampus. Results: Rats that were treated with SUVN-D1108121, spent significantly more time with the novel object in comparison to the familiar object at the tested doses of 0.01-0.1 mg/kg, p.o. Scopolamine at a dose of 0.8 mg/kg reduced the choice accuracy in the radial maze and increased the total error. SUVN-D1108121 at doses of 0.1-1 mg/kg increased the choice accuracy and decreased in the total error. An inverted U dose response curve was obtained in the radial maze. An increase in the brain Ach levels of more than 200% was observed in the frontal cortex and in the hippocampus. Conclusions: SUVN-D1108121 was found to reverse the time induced and scopolamine induced memory deficit. The active dose of SUVN-D1108121 was as low as 0.01 mg/kg, p.o. in the ORT. Preliminary studies through brain microdialysis indicate that the reversal in memory deficit could be through an increase in the acetylcholine levels in brain regions responsible for learning and memory.
Background: Alzheimer’s disease is a neurodegenerative disorder with cognitive decline and synaptic loss. Increasing evidence indicates that factors such as oxidative stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer’s disease pathogenesis. Sesamol (5-hydroxy-1,3- benzodioxole or 3,4-methylenedioxyphenol) is a potent antioxidant and anti-inflammatory molecule. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer’s disease. The present study was designed to explore the effect of solid lipid nanoparticles (SLNs) of sesamol versus plain sesamol against intracerebroventricular streptozotocin-induced cognitive impairment in rats. Methods: Streptozotocin (3 mg/kg) was administered intracerebroventricularly to male Wistar rats twice on days 1 and 3. The rats were treated with sesamol plain and its SLN’s (4, 8 & 16 mg/kg, peroral) for 21 days starting from day 1 of STZ injection. After 21 days, animals were sacrificed and the brains were isolated for different biochemical and cytokines estimations. Results: Intracerebroventricular streptozotocin (ICV-STZ) produced significant cognitive deficits coupled with increased acetylcholinesterase activity, marked oxidative-nitrergic stress and elevated inflammatory cytokines. SLN’s of sesamol and plain sesamol (4, 8 and 16 mg/kg; peroral) supplementation significantly and dose-dependently improved cognitive impairment, reduced acetylcholinesterase activity, attenuated oxidative-nitrergic stress and inflammatory cytokines in ICV-STZ administered rats. SLNs of sesamol in the dose of 16 mg/kg were found to be most potent in improving all behavioral and biochemical indices and the efficacy was comparable to rivastigmine. Conclusions: Our findings demonstrate that solid lipid nanoparticles of sesamol could be used as potential therapeutic and brain targeting strategy to combat the global burden of Alzheimer’s disease.
P1-265
NEUROPROTECTIVE POTENTIAL OF SOLID LIPID NANOPARTICLES OF SESAMOL: POSSIBLE BRAIN TARGETING STRATEGY
Shubham Misra1, Anurag Kuhad2, Indupal Kaur2, Kanwaljit Chopra2, Panjab University, Chandigarh, India; 2Univ Inst Pharm Sci, Panjab University, Chandigarh, India.
1
EFFECTS OF RIVASTIGMINE IN THE TREATMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF ALZHEIMER’S DISEASE
Vladimir Janjic, Slavica Djukic Dejanovic, Branimir Radmanovic, Clinical Center Kragujevac, Kragujevac, Serbia. Background: Objective of this work is to investigate the effects of rivastigmine, a dual inhibitor of acetyl cholinesterase and butyrylcholinesterase, in decreasing and/or eliminating behavioral symptoms in patients with Alzheimer’s disease. Methods: Investigation included 37 patients with Alzheimer’s disease who have been treated with rivastigmine with gradual increase of doses to maximum average dose of 9,3 mg/d. Behavioral and psychological symptoms were assessed in patients by using the 12 item Neuropsychiatric inventory (NPI), at the beginning of the treatment, after 6 months and after 12 months. Results: Our results show statistically significant improvement of total score on NPI scale after 6 (P <0.05) and after 12 (P ¼ 0.001) months of following. After 6 months of treatment, significant improvement was noticed for following symptoms: irritability, anxiety, night restlessness and delusions, and after 12 months the improvement was noticed for symptoms: irritability, hallucinations, delusions, nigh restlessness and agitation. Conclusions: Based on obtained data we conclude that rivastigmine is an efficient medicine in treatment of behavioral and psychological symptoms of Alzheimer’s disease during the six-month and the one-year treatment.
P1-266 P1-264
P199
NEUROPROTECTIVE EFFECTS OF LITHIUM ON SCOPOLAMINEINDUCED AMNESIA THROUGH DECREASING QUINONE REDUCTASE 2 IN RATS
Yuanyuan Wu, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.