Cortical hemorrhage‐associated neurological deficits and tissue damage in mice are ameliorated by therapeutic treatment with nicotine

Abstract

Intracerebral hemorrhage (ICH) is associated with diverse sets of neurological symptoms and prognosis, depending on the site of bleeding. Relative rate of hemorrhage occurring in the cerebral cortex (lobar hemorrhage) has been increasing, but there is no report on effective pharmacotherapeutic approaches for cortical hemorrhage either in preclinical or clinical studies. The present study aimed to establish an experimental model of cortical hemorrhage in mice for evaluation of effects of therapeutic drug candidates. Type VII collagenase at 0.015 U, injected into the parietal cortex, induced hemorrhage expanding into the whole layer of the posterior parts of the sensorimotor cortex in male C57BL/6 mice. Mice with ICH under these conditions exhibited significant motor deficits as revealed by beam-walking test. Daily administration of nicotine (1 and 2 mg/kg), with the first injection given at 3 hr after induction of ICH, improved motor performance of mice in a dose-dependent manner, although nicotine did not alter the volume of hematoma. Immunohistochemical examinations revealed that the number of neurons was drastically decreased within the hematoma region. Nicotine at 2 mg/kg partially but significantly increased the number of remaining neurons within the hematoma at 3 days after induction of ICH. ICH also resulted in inflammatory activation of microglia/macrophages in the perihematoma region, and nicotine (1 and 2 mg/kg) significantly attenuated the increase of microglia. These results suggest that nicotine can provide a therapeutic effect on cortical hemorrhage, possibly via its neuroprotective and anti-inflammatory actions. © 2017 Wiley Periodicals, Inc.

MiRNA-494 enhances M1 macrophage polarization via Nrdp1 in ICH mice model

“…Macrophage M1/M2 polarization have been identified in various central nervous system diseases, such as traumatic brain injury, spinal cord injury, and ischemic stroke [25][26][27]. The activation of macrophages occurs in the hemorrhagic brain and leads to inflammatory damage following ICH [28][29][30]. However, the specific mechanisms underlying macrophage polarization following ICH have not been well studied.…”

Cigarette Smoking History and Functional Outcomes After Spontaneous Intracerebral Hemorrhage

“…Nicotine, an agonist of the α−7 nicotinic acetylcholine receptor (α7-nAChR), has been investigated in several animal models of ICH as a potential neuroprotective agent that mediates the cholinergic anti-inflammatory pathway. [8][9][10][11][12] These studies reported decreased neuronal cell death and infiltration of inflammatory cells into the perihematomal area in subjects administered an α7-nAChR agonist, with resultant improvements in sensorimotor function and animal survival. [9][10][11][12] Despite its many detrimental consequences, including potential associations with increased ICH risk, cigarette smoking may have paradoxical neuroprotective effects in patients presenting with ICH via the cholinergic anti-inflammatory pathway mediated by the nicotine content found in cigarettes.…”

“…[8][9][10][11][12] These studies reported decreased neuronal cell death and infiltration of inflammatory cells into the perihematomal area in subjects administered an α7-nAChR agonist, with resultant improvements in sensorimotor function and animal survival. [9][10][11][12] Despite its many detrimental consequences, including potential associations with increased ICH risk, cigarette smoking may have paradoxical neuroprotective effects in patients presenting with ICH via the cholinergic anti-inflammatory pathway mediated by the nicotine content found in cigarettes. [13][14][15][16][17][18][19] However, the relationship between smoking status and post-ICH outcomes has not been rigorously investigated.…”

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

“…On the other hand, the relative incidence of non-hypertension-associated ICH that occurs in the cerebral cortex (cortical or lobar hemorrhage) has been increasing in recent years, but therapeutic approaches for cortical hemorrhage have been poorly explored. We addressed whether nicotine can provide therapeutic effect in cortical hemorrhage in mice (Anan et al 2017). Collagenase injection into the parietal cortex induced hemorrhage, which resulted in motor deficits in mice.…”