Neuroprotective effects of amiodarone in a mouse model of ischemic stroke

Kotoda, Masakazu; Ishiyama, Tadahiko; Mitsui, Kazuha; Hishiyama, Sohei; Matsukawa, Takashi

doi:10.1186/s12871-017-0459-3

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…In addition to working directly on cardiac tissue to reverse the ventricular arrhythmia, Amiodarone has been shown to alter cerebral chemical channels too [53]. Using a stroke mouse model, Kotoda et al [53] showed that the administration of Amiodarone prior to initiating a stroke was neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

Causal Link between Ventricular Ectopy and Concussion

Neary

Singh

Christiansen

et al. 2020

Case Reports in Medicine

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We present a unique case study report of a male individual with a history of mild nonischaemic cardiomyopathy, with no ventricular ectopy, that at the age of 76 years sustained multiple concussions (i.e., mild traumatic brain injury) within a week of each other. Concussion symptoms included cognitive difficulties, “not feeling well,” lethargy, fatigue, and signs of depression. He was later medically diagnosed with postconcussion syndrome. The patient, WJT, was referred for cardiac and neurological assessment. Structural neuroimaging of the brain (MRI) was unremarkable, but electrocardiography (ECG) assessments using a 24-hour Holter monitor revealed significant incidence of ventricular ectopy (9.4%; 9,350/99,836 beats) over a period of 5–6 months after injury and then a further increase in ventricular ectopy to 18% (15,968/88,189 beats) during the subsequent 3 months. The patient was then prescribed Amiodarone 200 mg, and his ventricular ectopy and concussion symptoms completely resolved simultaneously within days. To the authors’ knowledge, our study is the first to show a direct link between observable and documented cardiac dysregulation and concussion symptomology. Our study has important implications for both cardiac patients and the patients that sustain a concussion, and if medically managed with appropriate pharmacological intervention, it can reverse ventricular ectopy and concussion symptomology. More research is warranted to investigate the mechanisms for this dramatic and remarkable change in cardiac and cerebral functions and to further explore the brain-heart interaction and the intricate autonomic interaction that exists between the extrinsic and intracardiac nervous systems.

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Section: Discussionmentioning

confidence: 99%

Causal Link between Ventricular Ectopy and Concussion

Neary

Singh

Christiansen

et al. 2020

Case Reports in Medicine

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“…The Blockade of sodium channels can also be neuroprotective. As we previously reported, pre-treatment, but not post-treatment, with amiodarone attenuates brain injury after ischemic stroke by blocking the voltage-gated sodium channel [12]. Whether amiodarone acts on the neuroprotective side or detrimental side is likely to be dependent on the clinical and pathophysiological condition.…”

Section: Discussionmentioning

confidence: 97%

“…Two mice were excluded due to the death before 24 h after induction (one per each group); eight mice were included in each group. The amiodarone dose was chosen based on the body surface area [11] and previously published data [12]. The rectal temperature was monitored and maintained at 37 ± 0.5 °C using a heating pad.…”

Section: Methodsmentioning

confidence: 99%

Amiodarone exacerbates brain injuries after hypoxic–ischemic insult in mice

et al. 2019

Self Cite

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BackgroundSodium ion transportation plays a crucial role in the pathogenesis of hypoxic–ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx–efflux balance of sodium ion in the hypoxic–ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic–ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia–ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic–ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic–ischemic brain injury using a murine experimental model.ResultsCompared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic–ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic–ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm3, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups.ConclusionsAmiodarone exacerbated brain injuries and neurological outcomes after hypoxic–ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic–ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.

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“…Only turns involving full rearing along either board were recorded. This test was used to assess the sensorimotor and postural function [28].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury

Min

et al. 2019

IJMS

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Neonatal hypoxia–ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK β in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK β knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK β KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood–brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK β inhibition. In conclusion, inhibition of CaMKK β exacerbated neonatal hypoxia–ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic–ischemic brain injury.

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Neuroprotective effects of amiodarone in a mouse model of ischemic stroke

Cited by 13 publications

References 34 publications

Causal Link between Ventricular Ectopy and Concussion

Causal Link between Ventricular Ectopy and Concussion

Amiodarone exacerbates brain injuries after hypoxic–ischemic insult in mice

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury

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