Here are the 4 abstracts being presented at Neuroscience 2014
Presentation Abstract
Program#/Poster#: 41.07/D32
Presentation Title: Beneficial effects of anatabine in a mouse model of tauopathy
Location: WCC Hall A-C
Presentation time: Saturday, Nov 15, 2014, 1:00 PM - 5:00 PM
Presenter at Poster: Sat, Nov. 15, 2014, 3:00 PM - 4:00 PM
Topic: ++C.02.d. Tau: Animal models
Authors: *D. PARIS1, D. BEAULIEU-ABDELAHAD1, G. AIT-GHEZALA1, V. MATHURA1, M. VERMA1, A. E. ROHER2, F. CRAWFORD1, M. MULLAN1,3;
1Roskamp Inst., SARASOTA, FL; 2The Longtine Ctr. for Neurodegenerative Biochem., Banner Sun Hlth. Res. Inst., Sun City, AZ; 3Rock Creek Pharmaceuticals, Sarasota, FL
Abstract: We have previously shown that the natural alkaloid anatabine displays some anti-inflammatory and Alzheimer ß-amyloid lowering properties in the central nervous system associated with reduced STAT3, NF?B and microglial activation. Microglial activation and astrogliosis are preeminent in tauopathies and mitigation of neuroinflammation has been shown to delay the progression of tauopathies in animal models. We therefore investigated here the impact of a chronic oral treatment with anatabine in a mouse model of tauopathy (Tg P301S). We found that the incidence of paralysis and abnormal hind limb extension reflex was reduced in Tg Tau P301S treated with anatabine suggesting that anatabine delays the disease progression in this model of tauopathy. Additionally, we show that anatabine suppresses tau phosphorylation (at multiple Alzheimer's disease pertinent epitopes) as well as tau oligomerization in the brain and spinal cord of Tg P301S further confirming this assumption. The reduction in pathological tau species observed in anatabine treated mice was accompanied by a reduction in microgliosis and STAT3 activation in the brain and spinal cord of Tg P301S revealing an anti-inflammatory activity of anatabine in Tg P301S mice. Additional data regarding the mechanism(s) of action of anatabine responsible for its beneficial activity against the development of tauopathy will be presented. Overall our data support further exploration of anatabine as a disease modifying agent for the treatment of tauopathies including Alzheimer's disease. Possible competing interests: MM is the CEO of Rock Creek Pharmaceuticals which sells anatabine as a nutraceutical supplement. The anatabine used in this study was provided by Rock Creek Pharmaceuticals. None of the other authors receive remuneration from Rock Creek Pharmaceuticals. This study was funded by the Roskamp foundation.
Disclosures: D. Paris: None. D. Beaulieu-Abdelahad: None. G. Ait-Ghezala: None. V. Mathura: None. M. Verma: None. A.E. Roher: None. F. Crawford: None. M. Mullan: A. Employment/Salary (full or part-time):; Rock Creek Pharmaceuticals.
Keyword (s): NEUROINFLAMMATION
TAU
TRANSGENIC MICE
Presentation Abstract
Program#/Poster#: 307.17/D63
Presentation Title: Effects of anatabine on Alzheimer's disease (AD) like pathology, neuroinflammation and behavior in a transgenic mouse model of AD
Location: WCC Hall A-C
Presentation time: Monday, Nov 17, 2014, 8:00 AM -12:00 PM
Presenter at Poster: Mon, Nov. 17, 2014, 8:00 AM - 9:00 AM
Topic: ++C.02.k. Alzheimer's disease: In vivo approaches in animals
Authors: *M. VERMA;
Roskamp Inst., Sarasota, FL
Abstract: The impact of a chronic oral treatment with anatabine (a minor alkaloid present in plants of the Solanacea family) was investigated in wild-type mice and in a transgenic mouse model of AD (Tg PS1/APPsw). The treatment was initiated in 10 month-old animals (when Tg PS1/APPsw mice already display abundant Aß deposits and cognitive impairments) and lasted for 6.5 months. We found that anatabine prevented disinhibition in Tg PS1/APPsw mice and inhibited anxiety in wild-type mice. Tg PS1/APPsw mice also elicited profound social interaction and social memory deficits which were both alleviated by the anatabine treatment whereas anatabine had no significant impact on social behavior in wild-type mice. Pathological examinations of Tg PS1/APPsw brains at the completion of the study revealed that anatabine reduced brain Aß deposition and microgliosis. We observed an elevation in STAT3 phosphorylation in the brain of Tg PS1/APPsw compared to wild-type mice and found that anatabine prevented STAT3 activation in Tg PS1/APPsw brains. In addition to its role in the regulation of cytokines production and glial activation, STAT3 is also known to regulate BACE-1 expression. We therefore analyzed the possible impact of anatabine on BACE-1 mRNA expression. We found that anatabine significantly suppresses BACE-1 transcription in Tg PS1/APPsw brain providing a possible mechanism for the reduction in brain Aß burden observed. Overall our study shows that a chronic active treatment with anatabine reduces pathological Aß deposition, microgliosis, neuroinflammation and behavioral deficits in a Tg PS1/APPsw mouse model of AD. Potential Competing Interests: Anatabine was supplied for this research by Rock Creek Pharmaceuticals who sell anatabine as a dietary supplement. MM is the CEO of Rock Creek Pharmaceuticals. The Roskamp Institute is a not-for-profit public charity and none of the other authors listed received remuneration from Rock Creek Pharmaceuticals. This study was funded by the Roskamp foundation.
Disclosures: M. Verma: C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); Anatabine was supplied for this research by Rock Creek Pharmaceuticals who sell anatabine as a dietary supplement..
Keyword (s): ALZHEIMER'S DISEASE
AMYLOID
NEUROINFLAMMATION
Presentation Abstract
Program#/Poster#: 423.09/Z2
Presentation Title: Anatabine ameliorates cognitive impairment and neuropathological deficits in a mouse model of Gulf War Illness
Location: WCC Hall A-C
Presentation time: Monday, Nov 17, 2014, 1:00 PM - 5:00 PM
Presenter at Poster: Mon, Nov. 17, 2014, 1:00 PM - 2:00 PM
Topic: ++C.11.g. Neurotoxicity and neurodegeneration
Authors: *G. AIT-GHEZALA1,2,3, Z. ZAKIROVA1,2,3, B. MOUZON1,2,3, M. TWEED1,2,3, D. PARIS1,2,3, V. MATHURA1,2, F. CRAWFORD1,2,3, M. MULLAN1,4;
1Roskamp Inst., SARASOTA, FL; 2The Open University,Walton Hall, Milton Keynes,, Buckinghamshire MK7 6AA,, United Kingdom; 3James A. Haley Veteran’s Hospital, 13000 Bruce B. Downs Blvd., Tampa, FL; 4Rock Creek Pharmaceuticals,, Sarasota, FL
Abstract: Gulf War Illness (GWI) is a multisymptom chronic illness with a central nervous system (CNS) component, symptoms of which include cognitive impairment such as memory and neurological deficits, fatigue, and musculoskeletal problems, as well as immune and inflammatory dysfunction, as key consequences of exposure post deployment to the Persian Gulf War. There are ample data that suggest that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI. We have previously demonstrated that C57BL6/J mice at 5 months post exposure to GW agents early in life develop late-onset cognitive impairment, and neuropathological changes marked by an elevation of neuroinflammatory markers. This model of chronic consequences of acute exposure to GW agents is thus relevant to the veterans currently suffering with GWI as their exposure occurred over 20 years ago. We have previously shown in vitro and in vivo the efficacious anti-inflammatory properties of Anatabine, a minor tobacco alkaloid also present in plants of the Solanacea family, which displays a chemical structural similarity with nicotine (Paris et al., 2013). In the current study we investigated whether daily oral administration of Anatabine (2o mg/kg) could be used to mitigate neuroinflammation, and ameliorate cognitive impairment and neuropathological deficits observed in our mouse model of GWI. Behavioral analyses of learning and memory were performed in control and GW agent exposed mice at 5 months post-exposure, at the end of behavior assessment, a treatment or placebo began and the mice were assessed again 1 and 2 months post treatment with Anatabine. Our results demonstrate that 2 months post treatment with Anatabine we were able to rescue the neurobehavioral deficits we previously observed in these mice. Immunohistochemical (IHC) analyses are ongoing in brain sections from these animals. Thus, Anatabine is a promising potential therapeutic that may be used alleviate some of the symptoms experienced by GW veterans today. Possible competing interests: MM is the CEO of Rock Creek Pharmaceuticals which sells anatabine as a nutraceutical supplement. The anatabine used in this study was provided by Rock Creek Pharmaceuticals. None of the other authors receive remuneration from Rock Creek Pharmaceuticals. This study was funded by a CDMRP Grant to GAG.
Disclosures: G. Ait-Ghezala: None. Z. Zakirova: None. B. Mouzon: None. M. Tweed: None. D. Paris: None. V. Mathura: None. F. Crawford: None. M. Mullan: A. Employment/Salary (full or part-time):; Rock Creek Pharmaceuticals, Sarasota, Florida, USA..
Keyword (s): ASTROCYTE
NEUROINFLAMMATION
NICOTINE
Support: Congressionally Directed Medical Research Program Grant #:GW100076
Presentation Abstract
Program#/Poster#: 486.02
Presentation Title: Delayed treatment with Anatabine after repetitive mild TBI normalizes spatial memory impairment
Location: WCC 156
Presentation time: Tuesday, Nov 18, 2014, 8:15 AM - 8:30 AM
Topic: ++C.10.d. Brain: Therapeutic strategies
Authors: *S. FERGUSON1,2, B. MOUZON1,2, L. ABDULLAH1,2, G. CRYNEN1, V. MATHURA1, M. MULLAN1,2, F. CRAWFORD1,2;
1Roskamp Inst., Sarasota, FL; 2James A Haley Veteran's Hosp., Tampa, FL
Abstract: Traumatic brain injury (TBI) is a serious illness which on average strikes one person every 15 seconds in the US. TBI carries long term consequences, even after mild TBI, which are the most common and comprise as many as 75% of all TBI cases. Despite the mild nature of the initial insult, secondary injury neuroinflammatory and neurodegenerative processes are initiated and continue for weeks and months afterward. Previously we reported on the potential of anatabine to affect neuroinflammation and improve memory at a long term timepoint when taken acutely after mild TBI. We have characterized anatabine’s effects in a crossover study as a continuation of our previous work. We treated mice orally with anatabine in a closed head injury model of mild TBI. Anatabine was administered in their water starting 30 minutes after injury and continuing for 9 months. Untreated mice received regular water, and anesthesia controls were used for both the treated and untreated groups (r-sham). At a chronic timepoint 6 months after injury we saw a significant improvement of spatial memory of the anatabine treated r-mTBI mice compared to untreated r-mTBI mice, with anatabine treated r-mTBI mice performing as well as r-sham mice. At 9 months, 4 mice per group were euthanized for neuropathological analyses, revealing regionally-specific reductions in IBA1 and GFAP staining in the anatabine treated r-mTBI mice. We have continued to characterize the surviving mice using a crossover study design. Both r-mTBI and r-sham mice that were previously untreated were given anatabine starting at the 9 month timepoint. Mice that previously received anatabine began receiving regular water only. The mice were re-evaluated using the Barnes maze at 12 and 18 months post-injury. Although r-mTBI mice that began taking anatabine at 9 months post-TBI continued to perform worse than shams at the 12 month timepoint, by 18 months injured mice that had previously performed significantly worse than sham mice were now performing as well as shams. Pathological analysis of the brain tissue once again reveals regionally-specific differences that appear to be driven by anatabine treatment. Anatabine shows strong potential at improving memory following TBI, and may have a long therapeutic window, even to chronic timepoints; these data support further preclinical exploration of anatabine as a treatment for TBI. Dr. Michael Mullan is the CEO of Rock Creek Pharmaceuticals which sells anatabine as a nutraceutical supplement. The anatabine used in this study was provided by Rock Creek Pharmaceuticals. None of the other authors receive remuneration from Rock Creek Pharmaceuticals. This study was funded by the Roskamp foundation.
Disclosures: S. Ferguson: None. B. Mouzon: None. L. Abdullah: None. G. Crynen: None. V. Mathura: None. M. Mullan: A. Employment/Salary (full or part-time):; Rock Creek Pharmaceuticals. F. Crawford: None.
Keyword (s): TRAUMATIC BRAIN INJURY
TRAUMA
INFLAMMATION
Support: Roskamp Foundation
DoD Grant W81XWH-13-1-0253
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