Investigating Cardiac Morphological Alterations in a Pentylenetetrazol-Kindling Model of Epilepsy

Akyüz, Enes; Polat, Kristina Ayşe; Ateş, Şükrü; Unalmis, Demet; Tokpınar, Adem; Yılmaz, Seher; Kaymak, Emin; Doğanyiğit, Züleyha; Clara, Villa

doi:10.3390/diagnostics10060388

Cited by 10 publications

(12 citation statements)

References 25 publications

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“…Tissue samples obtained from rats exposed to the kindling model were determined with a 10% formaldehyde solution for use in histological examinations. After the detection process, routine tissue follow-up steps were applied to the tissues and embedded in paraffin to perform the paraffin blocks ( 10 ).…”

Section: Methodsmentioning

confidence: 99%

“…Tissue sections (5 μm) were obtained from the paraffin blocks and then placed on polylysine-coated slices for morphological analysis. The prepared slides were left in the oven for a certain period using standard histological methods as described in Akyuz et al ( 10 ). Xylene and paraffin were removed and passed through a graded alcohol series and diluted.…”

Section: Methodsmentioning

confidence: 99%

“…In this sense, cardiac hypertrophy seems to be related to the autonomic changes that arise from seizures, suggesting that the heart could be structurally affected, as observed in a chronic epileptic rat model ( 9 ). Structural cardiac pathologies can provide more insight into the SUDEP heterogeneous mechanisms ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

et al. 2021

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Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as “Epileptic Heart” and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the “Epileptic Heart” could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

et al. 2021

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“…PTZ injection was continued until seizure kindling was achieved, but never longer than 4 weeks. Seizure kindling was considered achieved when the animals showed a Score 4 or 5 after three consecutive injections of PTZ [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy

Akyüz

Doğanyiğit

Paudel

et al. 2021

Life

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Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.

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“…An increase in the immunoreactivity of Kir3.1 and muscarinic ACh receptor 2 (M2) was observed in the vagus nerve and heart tissue of epileptic rats (Akyuz, Doganyigit, et al., 2020). In addition, cardiac morphology studies performed in epileptic rats reported that the distance between the atria was found to be decreased, the overall heart weight was found to be increased, and a number of hemorrhagic areas were to be observed in the cardiac tissue (Akyuz, Polat, et al., 2020). Taken together, altered immunoreactivity of ACh‐associated Kir3.1 and M2 receptors on the heart and vagus nerve as well as the changing blood pressure and ECG findings (Figure 2) elucidate the mechanisms of cardiac pathologies that were associated with autonomic dysfunction in epilepsy.…”

Section: Cardiorespiratory Findingsmentioning

confidence: 99%

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology

Akyüz

Uner

Köklü

et al. 2021

J of Neuroscience Research

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Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy‐induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure‐induced damages in ANS‐control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy‐related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.

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Investigating Cardiac Morphological Alterations in a Pentylenetetrazol-Kindling Model of Epilepsy

Cited by 10 publications

References 25 publications

Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology

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