Elsevier

Neuroscience

Volume 222, 11 October 2012, Pages 10-19
Neuroscience

α7 Nicotinic acetylcholine receptor agonist attenuates neuropathological changes associated with intracerebral hemorrhage in mice

https://doi.org/10.1016/j.neuroscience.2012.07.024Get rights and content

Abstract

We have demonstrated previously that nicotine affords neuroprotective and anti-inflammatory effects against intracerebral hemorrhage (ICH)-associated neuropathological changes. The present study was undertaken to clarify whether subtype-specific agonists of nicotinic acetylcholine receptors (nAChRs) could preserve tissue integrity in mouse ICH model in vivo. ICH was induced by unilateral injection of collagenase into the striatum of male C57BL/6 mice. Daily intraperitoneal injection of α7 nAChR agonist PNU-282987 (3–10 mg/kg) for 3 days, starting from 3 h after induction of ICH, significantly increased the number of surviving neurons in the central and the peripheral regions of hematoma at 3 days after ICH. In contrast, α4β2 nAChR agonist RJR-2403 (2–10 mg/kg) given in the same regimen showed no significant effect. PNU-282987 and RJR-2403 did not affect either the size of hemorrhage or the extent of brain edema associated with ICH. PNU-282987 decreased the number of activated microglia/macrophages accumulating in the perihematoma region at 3 days after ICH, in a dose-dependent manner. On the other hand, the number of microglia/macrophages in the central region of hematoma at early phase of pathology (6 h after ICH) was increased by 10 mg/kg PNU-282987. These results suggest that α7 nAChR agonist can provide neuroprotective effect on ICH-induced injury, independently of its anti-inflammatory actions.

Highlights

► Effects of nicotinic receptor agonists on hemorrhagic injury were examined. ► α7 nicotinic receptor agonist PNU-282987 protected striatal neurons. ► PNU-282987 inhibited activation of microglia/macrophages in the perihematoma region. ► PNU-282987 had no effect on hematoma expansion and edema formation.

Introduction

Intracerebral hemorrhage (ICH) results from leakage of blood into brain parenchyma by rupture of blood vessels. This neurological disorder is characterized by high mortality and severe motor dysfunctions associated with brain edema, inflammation and neurodegeneration (Qureshi et al., 2009). Although several therapeutic interventions including regulation of osmotic pressure are in clinical practice, neuroprotective drug therapies have not been established to date (Katsuki, 2010). In the brain suffering ICH, inflammation and neurodegeneration are induced by several blood constituents such as thrombin and hemoglobin. These blood constituents triggers inflammatory responses accompanied by activation of microglia/macrophages (Möller et al., 2000, Fujimoto et al., 2006, Cai et al., 2011). Several lines of evidence indicate that suppression of activation of microglia/macrophages is a promising approach to improve ICH pathologies (Ohnishi et al., 2007, Wasserman and Schlichter, 2007). In fact, therapeutic agents that aim at suppressing microglia/macrophage activation and simultaneously preventing neuron loss are being explored (Lee et al., 2006, Matsushita et al., 2011).

Nicotinic acetylcholine receptors (nAChRs) are expressed not only in neurons but also in microglia/macrophages. Previous studies have demonstrated that stimulation of nAChRs by nicotine suppresses activation of microglia/macrophages (Suzuki et al., 2006, Ohnishi et al., 2008). In addition, stimulation of nAChRs may produce direct neuroprotective effect in various neurodegenerative disease models (Mudo et al., 2006). Neuroprotective effect of nicotine may be mediated by upregulation of an anti-apoptotic protein, B cell lymphoma-2 (Tait and Green, 2010), via phosphatidylinositol 3-kinase/Akt pathway that lies downstream of α7 nAChRs (Kihara et al., 2001). We have reported recently that daily intraperitoneal administration of nicotine in mice from 3 h after induction of ICH ameliorated neuropathological changes associated with hematoma (Hijioka et al., 2011). The effect of nicotine was featured by an increased number of surviving striatal neurons in the central region of hematoma, and by a decreased number of activated microglia/macrophages in the perihematoma region. On the other hand, nicotine showed no significant effect on expansion of hematoma and formation of brain edema (Hijioka et al., 2011).

Our previous study (Hijioka et al., 2011) was focused on the effect of nicotine, and which subtype of nAChRs plays an important role in ameliorating ICH pathology remained undetermined. Therefore, the present study was aimed to clarify whether subtype-specific nAChR agonists can reproduce the effect of nicotine in mouse ICH model. For this purpose, we used PNU-282987, a specific α7 nAChR agonist, and RJR-2403, a specific α4β2 nAChR agonist (Papke et al., 2000, Walker et al., 2006). Both α7 and α4β2 are major subtypes of nAChRs distributed in the central nervous system, and these receptor subtypes are implicated in neuroprotection and regulation of inflammation (Suzuki et al., 2006, Ohnishi et al., 2008, Akaike et al., 2010).

Section snippets

Mouse model of ICH

All procedures were approved by our institutional ethics committee concerning animal experiments, and animals were treated in accordance with the Guidelines of the United States National Institutes of Health regarding the care and use of animals for experimental procedures. Male C57BL/6J mice at 8–10 weeks of age weighing 22–28 g were used to produce collagenase-induced model of ICH, as described previously (Hijioka et al., 2011, Matsushita et al., 2011). Animals were maintained at constant

α7 nAChR receptor agonist PNU-282987 inhibits ICH-induced neuron loss

In the first set of experiments, we compared neuroprotective effects of nAChR agonists. As reported in our previous study (Hijioka et al., 2011), the number of NeuN-positive cells in both the center of the hematoma (central region) and the region adjacent to the intact area (peripheral region) was decreased substantially at 3 days after induction of ICH (Fig. 1A). Daily administration of nicotine (2 mg/kg) or α7 nAChR agonist PNU-282987 (10 mg/kg), starting from 3 h after induction of ICH,

Discussion

The present study was conducted to reveal whether subtype-specific nAChR agonists could mimic the effect of nicotine on ICH pathogenesis in mice. The experiments were focused onto α7 and α4β2 subtypes of nAChRs, both of which have been implicated in neuroprotection (Akaike et al., 2010). For example, α7 nAChR stimulation blocks β-amyloid-induced neurotoxicity in cortical neurons (Kihara et al., 2001). On the other hand, nicotine-induced protection of nigrostriatal dopaminergic neurons against

Acknowledgements

This work was supported by The Smoking Research Foundation, Mitsubishi Pharma Research Foundation, and The Ministry of Education, Culture, Sports, Science and Technology, Japan (Grants-in-Aid for Scientific Research 20390026, 23117714, 24659118).

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