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

Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Neuroscience (Impact Factor: 3.33). 07/2012; 222:10-9. DOI: 10.1016/j.neuroscience.2012.07.024
Source: PubMed

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 (3-10mg/kg) for 3 days, starting from 3h 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 10mg/kg PNU-282987. These results suggest that α7 nAChR agonist can provide neuroprotective effect on ICH-induced injury, independently of its anti-inflammatory actions.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury is results in varying degrees of disability in a significant number of people annually. The mechanisms of cognitive dysfunction after traumatic brain injury have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noreadrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among traumatic brain injury researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in prior studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction following traumatic brain injury. In addition, we describe studies that utilize both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies.
    Journal of Neurotrauma 02/2015; DOI:10.1089/neu.2014.3445 · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracerebral hemorrhage (ICH) is featured by poor prognosis such as high mortality rate and severe neurological dysfunction. In humans, several valuables including hematoma volume and ventricular expansion of hemorrhage are known to correlate with the extent of mortality and neurological dysfunction. However, relationship between hematoma conditions and the severity of symptoms in animal ICH models has not been clarified. Here we addressed this issue by using 7-tesla magnetic resonance imaging (MRI) on collagenase-induced ICH model in mice. We found that the mortality rate and the performance in behavioral tests did not correlate well with the volume of hematoma. In contrast, when hemorrhage invaded the internal capsule, mice exhibited high mortality and showed poor sensorimotor performance. High mortality rate and poor performance in behavioral tests were also observed when hemorrhage invaded the lateral ventricle, although worsened symptoms associated with ventricular hemorrhage were apparent only during early phase of the disease. These results clearly indicate that invasion of the internal capsule or the lateral ventricle by hematoma is a critical determinant of poor prognosis in experimental ICH model in mice as well as in human ICH patients. MRI assessment may be a powerful tool to refine investigations of pathogenic mechanisms and evaluations of drug effects in animal models of ICH.
    PLoS ONE 07/2013; 8(7):e67691. DOI:10.1371/journal.pone.0067691 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There has been strong pre-clinical research on mechanisms of initial cell death and tissue injury in intracerebral hemorrhage (ICH). This data has led to the evaluation of several therapeutics for neuroprotection or the mitigation of early tissue damage. Most of these studies have been done in the rat. Also, there has been little study of the mechanisms of tissue repair and recovery. This review examines the testing of candidate therapeutics in mouse models of ICH for their effect on tissue protection and repair. This review will help the readers compare it to the extensively researched rat model of ICH and thus enhance work that are pending in mouse model.
    Metabolic Brain Disease 05/2014; 30(2). DOI:10.1007/s11011-014-9559-7 · 2.40 Impact Factor