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

Ferguson, Scott; Mouzon, Benoit; Paris, Daniel; Aponte, Destinee; Abdullah, Laila; Stewart, William Α.; Mullan, Michael; Crawford, Fiona

doi:10.1089/neu.2016.4636

Cited by 26 publications

(18 citation statements)

References 30 publications

(37 reference statements)

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“…Previously, we found that pharmacological inhibition of chronic microglial activation beginning 1month post-injury using either mGluR5 agonists or delayed aerobic exercise, reduced neurodegeneration and improves long-term motor and cognitive recovery (Byrnes et al, 2012;Piao et al, 2013). Thus, these, and other pre-clinical studies (Ferguson et al, 2017), provide evidence for an expanded therapeutic window for neuroprotection by targeting chronic post-traumatic neuroinflammatory responses.…”

Section: Discussionmentioning

confidence: 76%

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Henry

Ritzel

Barrett

et al. 2019

Preprint

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Chronic neuroinflammation with sustained microglial activation occurs following moderate-to-severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this translational study, we examined the effects of delayed depletion and subsequent repopulation of microglia on chronic neurodegeneration and functional recovery up to three months posttrauma. A CSF1R inhibitor, PLX5622, was administered to injured adult male C57Bl/6 mice at one month after controlled cortical impact to remove chronically activated microglia, and the inihibitor was withdrawn 1 week later to allow microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology, similar to that of sham control uninjured animals, whereas microglia in untreated injured animals showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBIassociated neuropathological changes at 3 months posttrauma; these included a smaller cortical lesion, reduced neuronal cell death in the injured cortex and ipsilateral hippocampus, and decreased NOX2-dependent reactive microgliosis. Furthermore, delayed depletion of microglia led to widespread changes in the cortical transcriptome, including alterations in gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity.PLX5622 treated animals showed significantly improved neurological recovery using a variety of complementary neurobehavioral evaluations.These included beam walk and rotorod tests for sensori-motor function, as well as Ymaze, novel object recognition, and Morris water maze tests to evaluate cognitive function. Together, our findings show that chronic phase removal of neurotoxic microglia using CSF1R inhibitors after experimental TBI can markedly reduce chronic neuroinflammation and neurodegeneration, as well as related long-term motor and cognitive deficits. Thus, CSF1R inhibition may provide a clinically feasible approach to limit posttraumatic neurodegeneration and neurological dysfunction following head injury.with neurobehavioral assessment and histology. Rodney M. Ritzel contributed with experimental design, collected and performed data analysis of flow cytometry; James P. Barrett contributed to data collection and PCR analysis; Sarah J. Doran contributed to data collection and IHC analysis; Yun Jiao performed nanostring data analysis; Jennie B. Leach contributed to nanostring data analysis; Gregory L. Szeto contributed to nanostring data analysis and manuscript preparation; Bogdan A. Stoica contributed with experimental design; Alan I. Faden contributed with manuscript preparation; David J. Loane contributed to study conception and design, and manuscript preparation. All authors read and approved the manuscript prior to submission.

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Section: Discussionmentioning

confidence: 76%

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Henry

Ritzel

Barrett

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Both interventions significantly reduced NOX2 expression in chronically activated microglia. These, and other preclinical studies (Ferguson et al, 2017), provide additional evidence for an expanded therapeutic window for TBI by targeting chronic posttraumatic neuroinflammatory responses.…”

Section: Discussionmentioning

confidence: 84%

Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

et al. 2020

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Chronic neuroinflammation with sustained microglial activation occurs following severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this preclinical study, we examined the effects of delayed depletion of chronically activated microglia on functional recovery and neurodegeneration up to 3 months postinjury. A CSF1R inhibitor, Plexxikon (PLX) 5622, was administered to adult male C57BL/6J mice at 1 month after controlled cortical impact to remove chronically activated microglia, and the inhibitor was withdrawn 1-week later to allow for microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology similar to that of Sham uninjured mice, whereas microglia in vehicle-treated TBI mice showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes at 3 months postinjury; these included a smaller cortical lesion, reduced hippocampal neuron cell death, and decreased NOX2and NLRP3 inflammasome-associated neuroinflammation. Furthermore, delayed depletion of chronically activated microglia after TBI led to widespread changes in the cortical transcriptome and altered gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity. Using a variety of complementary neurobehavioral tests, PLX5622-treated TBI mice also had improved long-term motor and cognitive function recovery through 3 months postinjury. Together, these studies demonstrate that chronic phase removal of neurotoxic microglia after TBI using CSF1R inhibitors markedly reduce chronic neuroinflammation and associated neurodegeneration, as well as related motor and cognitive deficits.

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“…Racemic anatabine was marketed as an herbal supplement called Anatabloc by Rock Creek Pharmaceuticals. Several studies supported by this company have shown that anatabine, in addition to its anti-inflammatory actions, has procognitive [40][41][42][43], neuro-protective [44], immune disease modulating [45,46], and smoking cessation actions. Anatabine partially substitutes for nicotine in drug discrimination behavioral assays but does not have the addictive potency of nicotine [47,48].…”

Section: Discussionmentioning

confidence: 99%

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

et al. 2020

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Many organisms possess "secondary" compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other "minor" compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S-and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

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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

Cited by 26 publications

References 30 publications

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

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