Anatabine lowers Alzheimer's Aβ production in vitro and in vivo

Paris, Daniel; Belin, David; Bachmeier, Corbin; Reed, Jon; Ait‐Ghezala, Ghania; Bishop, Alex; Chen, Jin; Mathura, Venkat; Crawford, Fiona; Mullan, Michael

doi:10.1016/j.ejphar.2011.09.019

Cited by 58 publications

(69 citation statements)

References 31 publications

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“…Our data therefore identify Syk as an important regulator of A␤ production both in vitro and in vivo. We show additionally that (Ϫ)-nilvadipine, as well as a selective Syk inhibitor, or a reduction of syk expression using shRNA all prevent NFB activation suggesting a possible mechanism for the reduction of BACE-1 transcription observed following Syk inhibition as NFB has been shown previously to play an important role in the regulation of BACE-1 transcription and expression (36,37,44,64). Because NFB is involved in the regulation of neuroinflammation and cytokine production, these data also suggest that Syk may serve as an important target for regulating neuroinflammation.…”

Section: Discussionmentioning

confidence: 96%

“…This prompted us to explore in further detail the mechanisms responsible for the A␤-lowering properties of nilvadipine and to identify a possible molecular target controlling both A␤ production, A␤ clearance across the BBB, and Tau hyperphosphorylation. As (Ϫ)-nilvadipine and racemic nilvadipine inhibit BACE-1 transcription, we evaluated whether (Ϫ)-nilvadipine was impacting NFB activation because NFB has been shown to play an important role in the regulation of BACE-1 transcription and expression (36,37,43,44). We observed that (Ϫ)-nilvadipine inhibits NFB activation in response to TNF␣ (Fig.…”

Section: In Vitro Effects Of Nilvadipine Enantiomers On A␤ Productionmentioning

confidence: 99%

“…The clones (83D04, 38G10, and 69F04) with the most profound silencing were chosen to evaluate the effect of Syk deficiency on NFB luciferase activity. Briefly, NFB activation was triggered with 10 ng/ml PMA for 24 h, and NFB luciferase activity was quantified by chemiluminescence using the Luc-Screen Extended Glow from Applied Biosystems with a Synergy HT chemiluminescence reader (Biotek) as we described previously (36,37). Similarly, a clone of 7W CHO cells overexpressing APP stably transfected with SYK shRNAs to knock down Syk expression was selected.…”

Section: Methodsmentioning

confidence: 99%

“…SH-SY5Y cells were grown in DMEM/F-12 medium supplemented with 10% serum and 1% penicillin/streptomycin/ fungizone. BACE-1 mRNA quantifications were performed by real time quantitative RT-PCR using the housekeeping gene GAPDH as a reference mRNA, and BACE-1 protein expression was analyzed by Western blots as we described previously (36,37). SH-SY5Y cells were treated with a dose range of BAY61-3606 for 30 min and 24 h to assess the impact of Syk inhibition on AKT phosphorylation and GSK3␤ Ser-9 phosphorylation by Western blots using phospho-selective Ser-9 GSK3␤ and phospho-Ser-473 AKT antibodies (Cell Signaling Technology) at 1:1,000 dilutions.…”

Section: Treatment Of Tg Tau P301s Mice With (ϫ)-Nilvadipine and Bay6mentioning

confidence: 99%

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The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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Background: Spleen tyrosine kinase (Syk) mediates microglial activation and neurotoxicity elicited by Alzheimer A␤ peptides. Results: Syk regulates A␤ production via NFB-dependent mechanisms and Tau phosphorylation by controlling the activation of glycogen synthase 3␤. Conclusion: Inhibition of Syk can interrupt the neuroinflammation, pathological A␤ accumulation, and Tau hyperphosphorylation in AD. Significance: Syk represents a therapeutic target for the key pathological lesions that define AD.

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Section: Discussionmentioning

confidence: 96%

Section: In Vitro Effects Of Nilvadipine Enantiomers On A␤ Productionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Treatment Of Tg Tau P301s Mice With (ϫ)-Nilvadipine and Bay6mentioning

confidence: 99%

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The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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“…20,21 In in vivo studies of the effects of anatabine in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, anatabine improved the clinical score and reduced hind limb paralysis. 22 Given its excellent bioavailability and anti-inflammatory actin, anatabine might have utility as a therapeutic agent after TBI.…”

Section: Introductionmentioning

confidence: 99%

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Ferguson

Mouzon

Paris

et al. 2017

Journal of Neurotrauma

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(2017) Acute or delayed treatment with anatabine improves spatial memory and reduces pathological sequelae at late time-points after repetitive mild traumatic brain injury. Journal of Neurotrauma, 34(8), pp. 1676Neurotrauma, 34(8), pp. -1691Neurotrauma, 34(8), pp. . (doi:10.1089Neurotrauma, 34(8), pp. /neu.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/131662/ Abstract Traumatic brain injury (TBI) has chronic and long term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to two years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated which involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI.Our model of r-mTBI involves a series of 5 mild impacts (midline impact at 5 m/s, 1mm strike depth, 200ms dwell time)with an interval of 48 hours. Anatabine treatment was administered starting 30 minutes after injury and delivered continuously through in the water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice were euthanized for pathological analysis which revealed reductions in astroglial (GFAP) and microglial (IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and effects of treatment termination. 9 months following crossover the remaining mice showed no effect of injury on their spatial memory, and while pathological analysis showed improvements in mice who had received delayed treatment, corpus callosum IBA1 increased in postcrossover placebo r-mTBI mice.These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury.

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Nicotine from edible Solanaceae and risk of Parkinson disease

Nielsen

Franklin

Longstreth

et al. 2013

Annals of Neurology

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Objective To test whether risk of Parkinson disease (PD) is associated with consumption of nicotine-containing edibles from the same botanical family as tobacco, Solanaceae, including peppers, tomatoes and potatoes. Methods In a population-based study with 490 newly diagnosed idiopathic PD cases diagnosed during 1992–2008 at the University of Washington Neurology Clinic or Group Health Cooperative in western Washington State and 644 unrelated, neurologically normal controls, we examined whether PD was associated with self-reported typical frequency of consumption of peppers, tomatoes, tomato juice and potatoes during adulthood, while adjusting for consumption of other vegetables, age, sex, race/ethnicity, tobacco use and caffeine. Results PD was inversely associated with consumption of all edible Solanaceae combined (relative risk [RR]=0.81, 95% confidence interval [CI] 0.65–1.01 per time per day), but not consumption of all other vegetables combined (RR=1.00, 95% CI 0.92–1.10). The trend strengthened when we weighted edible Solanaceae by nicotine concentration (ptrend=0.004). An inverse association was also evident for peppers specifically (ptrend=0.005). The potentially protective effect of edible Solanaceae largely occurred in men and women who had never used tobacco or who had smoked cigarettes <10 years. Interpretation Dietary nicotine or other constituents of tobacco and peppers may reduce PD risk. However, confirmation and extension of these findings is needed to strengthen causal inferences that could suggest possible dietary or pharmaceutical interventions for PD prevention.

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Anatabine lowers Alzheimer's Aβ production in vitro and in vivo

Cited by 58 publications

References 31 publications

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Nicotine from edible Solanaceae and risk of Parkinson disease

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