Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation

Paris, Daniel; Belin, David; Abdullah, Laila; Bachmeier, Corbin; Ait‐Ghezala, Ghania; Reed, Jon; Verma, Megha; Crawford, Fiona; Mullan, Michael

doi:10.1016/j.ejphar.2012.11.017

Cited by 50 publications

(71 citation statements)

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“…In particular, the originally treated r-mTBI mice showed an increase in latency to find the target hole between the 3 month and 9 month post-crossover timepoints In order to better understand the mechanism behind these changes, we examined STAT3 phosphorylation histologically as well. Anatabine has been shown to reduce phosphorylation of STAT3 and NF-kB, 20,21 which may be influencing microglial activation downstream from the axonal damage. Prior to treatment crossover, anatabine treated r-mTBI had fewer p-STAT3 positive cells in the corpus callosum than placebo treated r-mTBI mice, correlating well with their neuroinflammatory and spatial memory profiles.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…We have shown that anatabine lowers Aβ production and neuroinflammation both in vitro and in vivo suggesting it could be a useful therapeutic compound against AD, particularly as it readily crosses the blood-brain barrier [21][22][23]. Other studies have revealed that anatabine suppresses the induction of cycloxygenase-2 and inducible nitric oxide synthase in macrophage and reduces the incidence of tyroiditis in mice [24] further supporting an anti-inflammatory activity of anatabine in vivo.…”

Section: Introductionmentioning

confidence: 77%

“…This dosage was selected based on our previous studies showing that at this dose anatabine displays an anti-inflammatory activity in the CNS [21][22][23]. During the time course of the treatment (40 days), 25% of Tg Tau P301S placebo mice became paralyzed (3 out of 12) whereas none (0 out of 11) in the anatabine treatment group developed paralysis during the study duration ( Figure 1).…”

Section: Effects Of Anatabine On the Behavior And Motor Impairments Omentioning

confidence: 99%

“…We have previously identified anatabine, a natural alkaloid present in plants of the Solanacea family, as a novel anti-inflammatory compound antagonizing both STAT3 and NFkB activation [21][22][23]. We have shown that anatabine lowers Aβ production and neuroinflammation both in vitro and in vivo suggesting it could be a useful therapeutic compound against AD, particularly as it readily crosses the blood-brain barrier [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Anatabine Attenuates Tau Phosphorylation and Oligomerization in P301S Tau Transgenic Mice

Paris¹

2014

Brain Disord Ther

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We have previously shown that the natural alkaloid anatabine displays some anti-inflammatory and Alzheimer amyloid (Aβ) lowering properties in the central nervous system associated with reduced STAT3 and NFkB activation. We investigated here the impact of a chronic oral treatment with anatabine in a model of tauopathy. We found that anatabine reduces the incidence of paralysis and abnormal hind limb extension reflex while improving rotarod performances in P301S mutant human Tau transgenic mice (Tg Tau P301S) suggesting that anatabine delays the disease progression in this model of tauopathy. Analyzes of brain and spinal cord homogenates reveal that anatabine reduces tau phosphorylation at multiple pertinent Alzheimer's disease (AD) epitopes and decreases the levels of pathological tau conformers/oligomers in both detergent soluble and insoluble fractions. Pathological tau species reduction induced by anatabine was accompanied by decreased Iba1 expression suggesting a diminution of microgliosis in the brain and spinal cord of Tg Tau P301S mice. In addition, we found that anatabine administration increases phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3β, a primary tau kinase, associated with AD pathology, providing a possible mechanism for the observed reduction of tau phosphorylation. These data support further exploration of anatabine as a possible disease modifying agent for neurodegenerative tauopathies and, in particular AD, since anatabine also displays Aβ lowering properties.

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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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Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation

Cited by 50 publications

References 41 publications

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

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

Anatabine Attenuates Tau Phosphorylation and Oligomerization in P301S Tau Transgenic Mice

Nicotine from edible Solanaceae and risk of Parkinson disease

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