- Email: [email protected]
Muscarinic receptor 1 agonist activity of novel arecoline derivatives in Alzheimer's dementia models
Poster Presentations P1 meeting annual recruitment goals. There was no correlation between presence of recruitment staff and 1) preferred method of recruitment or 2) a center’s ability to meet recruitment goals. Furthermore, although all ADRCs have a website, few (35%) see it as an active tool for recruitment. Conclusions: These data suggest that successful recruitment is a result of a comprehensive recruitment plan. The successful ADRC 1) promotes study participation while conducting community educational events, and 2) partners with outside physicians. Those interviewed agreed that without the support of lay community and physicians, recruitment goals are not met. The successful ADRC has built their program using educational seminars, free screenings, and a willingness to serve to the community. P1-227
TREATMENT OF PARAPHILIC HYPERSEXUALITY IN DEMENTIA
Almir R. Tavares, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Contact e-mail: [email protected] Background: Paraphilic hypersexuality is a common source of suffering in neurodegenerative disorders, for patients and families. Few studies address this relevant subject. Recommended in paraphilic disorders of other nature, psychosocial interventions tend to be ineffective in the dementia patient. Thus, clinicians need to be aware of the pharmacologic options. Methods: An 89 years-old female, fragile, Alzheimer´s disease patient presented with a stroke of the territory of the left anterior cerebral artery (temporoparietal). After three weeks, a combination of aggitation and hypersexuality behaviours gradually appeared: she verbally expressed sexual interest in younger male around her, including some of her own family members, sometimes shouting; she proudly danced denuded; she masturbated openly. Results: Treatment with quetiapine was instituted. The dose was gradually titrated to 25 mg three times a day. After two weeks, hypersexuality behaviours disappeared and aggitation lessened. Such improvements favoured participation in rehabilitation activities. Conclusions: SSRI antidepressants are usually the initial drug treatment for mild cases of paraphilic hypersexuality in neurodegenerative disorders. However, this approach frequently fails. This patient was on escitalopram when hypersexual symtoms appeared. Quetiapine can be an option in such circunstance. Electrocardiographic monitoring is required, particularly regarding the duration of the QTc interval. When neuroleptics also fail, in severer cases of male paraphilic hypersexuality in dementias, agents influencing androgens are promissing: cyproterone, medroxyprogesterone, and leuprolide are the most cited. P1-228
MUSCARINIC RECEPTOR 1 AGONIST ACTIVITY OF NOVEL ARECOLINE DERIVATIVES IN ALZHEIMER’S DEMENTIA MODELS
P243
has shown very good affinity towards the M1 receptor in vitro and has also elicited beneficial effects in vivo memory and learning models. P1-229
EFFECTS OF ZINC PLUS CYCLO(HIS-PRO) ON PATHOLOGY, LEARNING AND MEMORY IN ATRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Stephen A. O’Barr1, Moon K. Song2, Kriscelle H. Mendoza1, Khanh N. Nguyen1, Delilah D. Shahidzadeh1, James J. Schultz2, 1Western University of Health Sciences, Pomona, CA, USA; 2Veterans Affairs Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Contact e-mail: sobarr@ westernu.edu Background: Memory loss is a major clinical hallmark of Alzheimer’s disease (AD), which currently affects over 26 million individuals worldwide. While the causes of AD are unknown, recent epidemiological studies show an increased risk of AD in both type 1 and type 2 diabetic patients. This may explain why mice given a high fat diet present with increased insulin resistance, enhanced amyloidosis and decreased levels of the zinc containing, Ab metabolizing, insulin degrading enzyme (IDE). Previous work from our group shows that treatment with a novel patented formulation of zinc plus cyclo(his-pro), named ZC, significantly improves insulin sensitivity in several diabetic animals models. As AD may be linked to diabetes, we recently tested ZC’s ability to alter Ab levels, IDE activity, as well as learning and memory in a transgenic mouse model of AD. Methods: Nine to twelve month old huAPP-YAC transgenic mice (R1.40 strain) were treated with 10 mg/L Zn plus 1.0 mg/L cyclo(his-pro) in water ad libitum, with controls receiving access to water alone ad libitum. At the end of five weeks of treatment, Ab levels and IDE activity were measured. Nine month old R1.40 mice, treated as previously described, were tested on a Barne’s Maze for learning and memory at baseline and at monthly intervals. Results: In this study we show that ZC decreases both cytosolic and membrane forms of Ab1-42 and Ab1-40, while enhancing IDE activity. Mice treated with ZC also show an increased ability to learn and remember the location of an escape hole. Conclusions: Here we demonstrate for the first time that a novel patented formulation decreases Ab levels, increases IDE activity, and enhances learning and memory in an AD transgenic mouse model. P1-230
CREATIVE WAYS TO CARE: A TRAINING PROGRAM ON THE USE OF THERAPEUTIC STRATEGIES FOR FAMILY CARERS WHO ARE LIVING WITH PEOPLE WHO HAVE BEHAVIOURAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA
K. S. Rangappa, University of Mysore, Mysore, India. Contact e-mail: [email protected]
Virginia A. Creaser, Commonwealth Respite and Carelink Centre, Melbourne, Australia. Contact e-mail: [email protected]
Background: The cholinergic deficit in Alzheimer’s disease (AD) patient’s brain has intensified research efforts to test cholinomimetic approaches for efficacy in AD therapy. Various therapies may be of potential clinical use in AD. Among these are cholinergic agents including muscarinic agonists, acetylcholinesterase inhibitors, and acetylcholine releasing agents. One of the muscarinic agonists tested in AD is arecoline and its bioisosters, which are widely explored as muscarinic receptor 1 agonist (M1 receptor agonist) in AD research. Methods: In this regard, we have synthesized five and six membranes heterocyclic ring system attached arecoline basic nucleus (N-methyl tetrahydropyridines) at 3rd position. Subsequently the synthesized arecolines derivatives were subjected to in vitro muscarinic receptor 1 binding affinity studies using male wistar rat brain synaptosomal membrane (cerebral cortex) and also cell line culture studies and extended this in vitro studies to in vivo pharmacological evaluation of memory and learning in male wistar rats (Rodent memory evaluation, plus and Y maze studies). Results: Some of our synthesized molecules have shown very potent M1 receptor agonist activity and significantly elevated the basal IP3 levels in vitro and also have decreased beta-amyloid (Abeta40 and Abeta42) deposition in cell lines culture. These molecules have also shown very good antidementia activity in rat dementia model. Conclusions: Molecules with electron donating group as a substitute,
Background: ‘Creative Ways to Care’ (CWTC) is an educational, multimedia training resource inclusive of a DVD and a Group Facilitator Training Manual. CWTC offers family carers the opportunity to learn a range of diversional therapy techniques to use at home which can assist with Behavioural and Psychological Symptoms of Dementia (BPSD) such as wandering, restlessness, repetitive questioning or behaviour, boredom and lack of motivation to initiate tasks. Methods: The Commonwealth Respite and Carelink Centre, Melbourne, Australia piloted CWTC as a one day workshop in 2007 with 35 carers. Following evaluation of the pilot the team modified CWTC. The DVD script and training manual was written by therapists in collaboration with a Reference Group. This model was then trialled by carers in a Focus Group in 2008 and the DVD and Training Manual was then further modified based on their feedback and from group facilitators, dementia specialists, Therapists, (eg Music and Art) and the Reference Group. The DVD features the approach in action, as well as diversional therapists and carers explaining why, what and how these strategies should be practiced. The Facilitators Training Manual consists of detailed notes which elaborate on running the workshops as well as offering background information on the strategies and frequently asked questions to assist the facilitator. CWTC Program: Family carers participate in six experiential and small group
TREATMENT OF PARAPHILIC HYPERSEXUALITY IN DEMENTIA
Almir R. Tavares, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Contact e-mail: [email protected] Background: Paraphilic hypersexuality is a common source of suffering in neurodegenerative disorders, for patients and families. Few studies address this relevant subject. Recommended in paraphilic disorders of other nature, psychosocial interventions tend to be ineffective in the dementia patient. Thus, clinicians need to be aware of the pharmacologic options. Methods: An 89 years-old female, fragile, Alzheimer´s disease patient presented with a stroke of the territory of the left anterior cerebral artery (temporoparietal). After three weeks, a combination of aggitation and hypersexuality behaviours gradually appeared: she verbally expressed sexual interest in younger male around her, including some of her own family members, sometimes shouting; she proudly danced denuded; she masturbated openly. Results: Treatment with quetiapine was instituted. The dose was gradually titrated to 25 mg three times a day. After two weeks, hypersexuality behaviours disappeared and aggitation lessened. Such improvements favoured participation in rehabilitation activities. Conclusions: SSRI antidepressants are usually the initial drug treatment for mild cases of paraphilic hypersexuality in neurodegenerative disorders. However, this approach frequently fails. This patient was on escitalopram when hypersexual symtoms appeared. Quetiapine can be an option in such circunstance. Electrocardiographic monitoring is required, particularly regarding the duration of the QTc interval. When neuroleptics also fail, in severer cases of male paraphilic hypersexuality in dementias, agents influencing androgens are promissing: cyproterone, medroxyprogesterone, and leuprolide are the most cited. P1-228
MUSCARINIC RECEPTOR 1 AGONIST ACTIVITY OF NOVEL ARECOLINE DERIVATIVES IN ALZHEIMER’S DEMENTIA MODELS
P243
has shown very good affinity towards the M1 receptor in vitro and has also elicited beneficial effects in vivo memory and learning models. P1-229
EFFECTS OF ZINC PLUS CYCLO(HIS-PRO) ON PATHOLOGY, LEARNING AND MEMORY IN ATRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Stephen A. O’Barr1, Moon K. Song2, Kriscelle H. Mendoza1, Khanh N. Nguyen1, Delilah D. Shahidzadeh1, James J. Schultz2, 1Western University of Health Sciences, Pomona, CA, USA; 2Veterans Affairs Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Contact e-mail: sobarr@ westernu.edu Background: Memory loss is a major clinical hallmark of Alzheimer’s disease (AD), which currently affects over 26 million individuals worldwide. While the causes of AD are unknown, recent epidemiological studies show an increased risk of AD in both type 1 and type 2 diabetic patients. This may explain why mice given a high fat diet present with increased insulin resistance, enhanced amyloidosis and decreased levels of the zinc containing, Ab metabolizing, insulin degrading enzyme (IDE). Previous work from our group shows that treatment with a novel patented formulation of zinc plus cyclo(his-pro), named ZC, significantly improves insulin sensitivity in several diabetic animals models. As AD may be linked to diabetes, we recently tested ZC’s ability to alter Ab levels, IDE activity, as well as learning and memory in a transgenic mouse model of AD. Methods: Nine to twelve month old huAPP-YAC transgenic mice (R1.40 strain) were treated with 10 mg/L Zn plus 1.0 mg/L cyclo(his-pro) in water ad libitum, with controls receiving access to water alone ad libitum. At the end of five weeks of treatment, Ab levels and IDE activity were measured. Nine month old R1.40 mice, treated as previously described, were tested on a Barne’s Maze for learning and memory at baseline and at monthly intervals. Results: In this study we show that ZC decreases both cytosolic and membrane forms of Ab1-42 and Ab1-40, while enhancing IDE activity. Mice treated with ZC also show an increased ability to learn and remember the location of an escape hole. Conclusions: Here we demonstrate for the first time that a novel patented formulation decreases Ab levels, increases IDE activity, and enhances learning and memory in an AD transgenic mouse model. P1-230
CREATIVE WAYS TO CARE: A TRAINING PROGRAM ON THE USE OF THERAPEUTIC STRATEGIES FOR FAMILY CARERS WHO ARE LIVING WITH PEOPLE WHO HAVE BEHAVIOURAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA
K. S. Rangappa, University of Mysore, Mysore, India. Contact e-mail: [email protected]
Virginia A. Creaser, Commonwealth Respite and Carelink Centre, Melbourne, Australia. Contact e-mail: [email protected]
Background: The cholinergic deficit in Alzheimer’s disease (AD) patient’s brain has intensified research efforts to test cholinomimetic approaches for efficacy in AD therapy. Various therapies may be of potential clinical use in AD. Among these are cholinergic agents including muscarinic agonists, acetylcholinesterase inhibitors, and acetylcholine releasing agents. One of the muscarinic agonists tested in AD is arecoline and its bioisosters, which are widely explored as muscarinic receptor 1 agonist (M1 receptor agonist) in AD research. Methods: In this regard, we have synthesized five and six membranes heterocyclic ring system attached arecoline basic nucleus (N-methyl tetrahydropyridines) at 3rd position. Subsequently the synthesized arecolines derivatives were subjected to in vitro muscarinic receptor 1 binding affinity studies using male wistar rat brain synaptosomal membrane (cerebral cortex) and also cell line culture studies and extended this in vitro studies to in vivo pharmacological evaluation of memory and learning in male wistar rats (Rodent memory evaluation, plus and Y maze studies). Results: Some of our synthesized molecules have shown very potent M1 receptor agonist activity and significantly elevated the basal IP3 levels in vitro and also have decreased beta-amyloid (Abeta40 and Abeta42) deposition in cell lines culture. These molecules have also shown very good antidementia activity in rat dementia model. Conclusions: Molecules with electron donating group as a substitute,
Background: ‘Creative Ways to Care’ (CWTC) is an educational, multimedia training resource inclusive of a DVD and a Group Facilitator Training Manual. CWTC offers family carers the opportunity to learn a range of diversional therapy techniques to use at home which can assist with Behavioural and Psychological Symptoms of Dementia (BPSD) such as wandering, restlessness, repetitive questioning or behaviour, boredom and lack of motivation to initiate tasks. Methods: The Commonwealth Respite and Carelink Centre, Melbourne, Australia piloted CWTC as a one day workshop in 2007 with 35 carers. Following evaluation of the pilot the team modified CWTC. The DVD script and training manual was written by therapists in collaboration with a Reference Group. This model was then trialled by carers in a Focus Group in 2008 and the DVD and Training Manual was then further modified based on their feedback and from group facilitators, dementia specialists, Therapists, (eg Music and Art) and the Reference Group. The DVD features the approach in action, as well as diversional therapists and carers explaining why, what and how these strategies should be practiced. The Facilitators Training Manual consists of detailed notes which elaborate on running the workshops as well as offering background information on the strategies and frequently asked questions to assist the facilitator. CWTC Program: Family carers participate in six experiential and small group