scholarly journals α7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Paul R. Krafft ◽  
Devin McBride ◽  
William B. Rolland ◽  
Tim Lekic ◽  
Jerry J. Flores ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Treatment Effects ◽  
Autologous Blood ◽  
Janus Kinase ◽  
Intracerebral Injection ◽  
Sprague Dawley ◽  
Nicotinic Acetylcholine

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whetherα7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received eitherα7nAChR agonist PHA-543613 alone or combined withα7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α(TNF-α), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF-αand MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490.α7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH.

Long-Term Nicotine Treatment Decreases Striatal α6* Nicotinic Acetylcholine Receptor Sites and Function in Mice

2005 ◽  
Vol 67 (5) ◽  
pp. 1639-1647 ◽  
Author(s):  
Albert Lai ◽  
Neeraja Parameswaran ◽  
Mirium Khwaja ◽  
Paul Whiteaker ◽  
Jon M. Lindstrom ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Nicotine Treatment ◽  
Receptor Sites ◽  
And Function

Abstract TP118: Activation of Alpha-7 Nicotinic Acetylcholine Receptor Improved Long-Term Cognitive Function of Mice With Long-Bone Fracture and Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Kang Hou ◽  
Meng Wei ◽  
Meng Zhang ◽  
Zhanqiang Wang ◽  
Sonali Shaligram ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Dentate Gyrus ◽  
Acetylcholine Receptor ◽  
Cognitive Dysfunction ◽  
Nicotinic Acetylcholine Receptor ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Nicotinic Acetylcholine ◽  
Y Maze

Introduction: Tibia fracture (BF) enhances stroke injury and when occurring 6 hrs before stroke (BF6+Stroke) causes long-lasting cognitive dysfunction in mouse. Activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced neuroinflammation, neuronal injury and sensorimotor dysfunction in mice with BF one day after stroke (Stroke+1BF). Hypothesis: Activation of α-7 nAchR improves long-term cognitive function of BF6+Stroke mice. Methods: BF6+Stroke mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and MLA (α-7 nAchR antagonist) treatment groups. The sensorimotor function were tested by adhesive removal and corner tests at 3 days, the cognitive function was tested by Y-maze weekly for 8 weeks and Novel Objective Recognition (NOR) at 8 weeks post-injuries. The neuronal damage, neuroinflammaiton, neurogenesis were analyzed 3 and/or 8 weeks post-injuries. Results: Similar to Stroke+1BF mice, PHA reduced and MLA enhanced neuronal injury, neuroinflammation, and sensorimotor dysfunction of BF6+Stroke mice. Further, PHA reduced and MLA enhanced their long-term cognitive dysfunction. In Y maze test, all mice made fewer alternations 1-week post-surgeries than baseline; PHA group recovered to baseline at week 5 post-surgeries; saline and MLA groups continuously made fewer alternations throughout the 8-weeks. In NOR test, PHA group spent more time, MLA group spent less time than saline group on novel objects. Injection of BrdU in the 2 nd week post-surgeries labeled more neurons in the contralateral than in the ipsilateral dentate gyrus in all groups; PHA group had the most, MLA group had the least BrdU + neurons. Injection BrdU in the 7th week post-surgeries did not labeled any neuron. Conclusion: Activation of α-7 nAchR decreased neuronal damage and neuroinflammation, increased neurogenesis at the dentate gyrus of BF6+Stroke mice; and improved their sensorimotor and long-term cognitive function.

scholarly journals Alpha-7 nicotinic acetylcholine receptor agonists in intracerebral hemorrhage: an evaluation of the current evidence for a novel therapeutic agent

2013 ◽  
Vol 34 (5) ◽  
pp. E10 ◽  
Author(s):  
Eric S. Sussman ◽  
Christopher P. Kellner ◽  
Michael M. McDowell ◽  
Samuel S. Bruce ◽  
Simon G. Heuts ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Therapeutic Agent ◽  
Current Evidence ◽  
Secondary Injury ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr ◽  
Alpha 7 ◽  
Novel Therapeutic

Intracerebral hemorrhage (ICH) is the most deadly and least treatable subtype of stroke, and at the present time there are no evidence-based therapeutic interventions for patients with this disease. Secondary injury mechanisms are known to cause substantial rates of morbidity and mortality following ICH, and the inflammatory cascade is a major contributor to this post-ICH secondary injury. The alpha-7 nicotinic acetylcholine receptor (α7-nAChR) agonists have a well-established antiinflammatory effect and have been shown to attenuate perihematomal edema volume and to improve functional outcome in experimental ICH. The authors evaluate the current evidence for the use of an α7-nAChR agonist as a novel therapeutic agent in patients with ICH.

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