scholarly journals TLR7 agonist modulation of postasphyxial neurophysiological and cardiovascular adaptations in preterm fetal sheep

2020 ◽  
Vol 318 (2) ◽  
pp. R369-R378 ◽  
Author(s):  
Kenta H. T. Cho ◽  
Mhoyra Fraser ◽  
Guido Wassink ◽  
Simerdeep J. Dhillon ◽  
Joanne O. Davidson ◽  
...  
Keyword(s):  
Vascular Function ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Cell Loss ◽  
High Amplitude ◽  
Fetal Sheep ◽  
Tlr Agonists ◽  
Intracerebroventricular Infusion ◽  
Tlr7 Agonist ◽  
Neuroprotective Strategies

Activation of Toll-like receptors (TLRs) after hypoxic-ischemic brain injury can exacerbate injury but also alleviate cell loss, as recently demonstrated with the TLR7 agonist Gardiquimod (GDQ). However, TLR agonists also modulate vascular function and neuronal excitability. Thus, we examined the effects of TLR7 activation with GDQ on cardiovascular function and seizures after asphyxia in preterm fetal sheep at 0.7 gestation (104 days, term ∼147 days). Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min or asphyxia followed by a continuous intracerebroventricular infusion of 3.34 mg of GDQ from 1 to 4 h after asphyxia. Fetuses were monitored continuously for 72 h postasphyxia. GDQ treatment was associated with sustained, moderate hypertension for 72 h ( P < 0.05), with a transient increase in heart rate. Electroencephalographic (EEG) power was suppressed for the entire postasphyxial period in both groups, whereas EEG spectral edge transiently increased during the GDQ infusion compared with asphyxia alone ( P < 0.05), with higher β- and lower δ-EEG frequencies ( P < 0.05). This increase in EEG frequency was not related to epileptiform activity. After the GDQ infusion, there was earlier onset of high-amplitude stereotypic evolving seizures, with increased numbers of seizures and seizure burden ( P < 0.05). Hemodynamic function and seizure activity are important indices of preterm wellbeing. These data highlight the importance of physiological monitoring during preclinical testing of potential neuroprotective strategies.

scholarly journals Induction of Tertiary Phase Epileptiform Discharges after Postasphyxial Infusion of a Toll-Like Receptor 7 Agonist in Preterm Fetal Sheep

2021 ◽  
Vol 22 (12) ◽  
pp. 6593
Author(s):  
Kenta H.T. Cho ◽  
Mhoyra Fraser ◽  
Bing Xu ◽  
Justin M. Dean ◽  
Alistair J. Gunn ◽  
...  
Keyword(s):  
Moderate Hypertension ◽  
Epileptiform Activity ◽  
Ischemic Brain Injury ◽  
Toll Like Receptor ◽  
Fetal Sheep ◽  
Ischemic Brain ◽  
Tlr Agonists ◽  
Epileptiform Discharges ◽  
Subcortical Regions ◽  
Total Burden

Background: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic–ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. Methods: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. Results: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). Conclusion: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.

scholarly journals Potassium diffusive coupling in neural networks

2010 ◽  
Vol 365 (1551) ◽  
pp. 2347-2362 ◽  
Author(s):  
Dominique M. Durand ◽  
Eun-Hyoung Park ◽  
Alicia L. Jensen
Keyword(s):  
Neural Networks ◽  
Neural Activity ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Lateral Diffusion ◽  
Normal Activity ◽  
Ionic Concentration ◽  
Extracellular Potassium ◽  
Potassium Accumulation ◽  
Diffusive Coupling

Conventional neural networks are characterized by many neurons coupled together through synapses. The activity, synchronization, plasticity and excitability of the network are then controlled by its synaptic connectivity. Neurons are surrounded by an extracellular space whereby fluctuations in specific ionic concentration can modulate neuronal excitability. Extracellular concentrations of potassium ([K + ] o ) can generate neuronal hyperexcitability. Yet, after many years of research, it is still unknown whether an elevation of potassium is the cause or the result of the generation, propagation and synchronization of epileptiform activity. An elevation of potassium in neural tissue can be characterized by dispersion (global elevation of potassium) and lateral diffusion (local spatial gradients). Both experimental and computational studies have shown that lateral diffusion is involved in the generation and the propagation of neural activity in diffusively coupled networks. Therefore, diffusion-based coupling by potassium can play an important role in neural networks and it is reviewed in four sections. Section 2 shows that potassium diffusion is responsible for the synchronization of activity across a mechanical cut in the tissue. A computer model of diffusive coupling shows that potassium diffusion can mediate communication between cells and generate abnormal and/or periodic activity in small (§3) and in large networks of cells (§4). Finally, in §5, a study of the role of extracellular potassium in the propagation of axonal signals shows that elevated potassium concentration can block the propagation of neural activity in axonal pathways. Taken together, these results indicate that potassium accumulation and diffusion can interfere with normal activity and generate abnormal activity in neural networks.

Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

2002 ◽  
Vol 87 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Marom Bikson ◽  
Scott C. Baraban ◽  
Dominique M. Durand
Keyword(s):  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Seizure Threshold ◽  
Ion Selective Electrodes ◽  
Receptor Antagonists ◽  
Sodium Conductance ◽  
Ca1 Region ◽  
Persistent Sodium Conductance

Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca2+ concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca2+ levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca2+ reduction in normal Ca2+ levels. Increasing neuronal excitability, by removing extracellular Mg2+ and increasing extracellular K+ (6–15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [d-(−)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of KCaantagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba2+) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg2+ and increasing extracellular K+) in the presence of Cd2+, a nonselective Ca2+channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca2+ facilitates bursting by increasing neuronal excitability and inhibiting Ca2+ influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca2+ levels.

scholarly journals Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep

2020 ◽  
Vol 21 (18) ◽  
pp. 6475
Author(s):  
Panzao Yang ◽  
Joanne O. Davidson ◽  
Tania M. Fowke ◽  
Robert Galinsky ◽  
Guido Wassink ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Perineuronal Nets ◽  
Perinatal Hypoxia ◽  
Perineuronal Net ◽  
Fetal Sheep ◽  
Mimetic Peptide ◽  
Intracerebroventricular Infusion ◽  
Bilateral Carotid ◽  
Cortical Interneurons ◽  
Hypoxia Ischemia

Perinatal hypoxia-ischemia is associated with disruption of cortical gamma-aminobutyric acid (GABA)ergic interneurons and their surrounding perineuronal nets, which may contribute to persisting neurological deficits. Blockade of connexin43 hemichannels using a mimetic peptide can alleviate seizures and injury after hypoxia-ischemia. In this study, we tested the hypothesis that connexin43 hemichannel blockade improves the integrity of cortical interneurons and perineuronal nets. Term-equivalent fetal sheep received 30 min of bilateral carotid artery occlusion, recovery for 90 min, followed by a 25-h intracerebroventricular infusion of vehicle or a mimetic peptide that blocks connexin hemichannels or by a sham ischemia + vehicle infusion. Brain tissues were stained for interneuronal markers or perineuronal nets. Cerebral ischemia was associated with loss of cortical interneurons and perineuronal nets. The mimetic peptide infusion reduced loss of glutamic acid decarboxylase-, calretinin-, and parvalbumin-expressing interneurons and perineuronal nets. The interneuron and perineuronal net densities were negatively correlated with total seizure burden after ischemia. These data suggest that the opening of connexin43 hemichannels after perinatal hypoxia-ischemia causes loss of cortical interneurons and perineuronal nets and that this exacerbates seizures. Connexin43 hemichannel blockade may be an effective strategy to attenuate seizures and may improve long-term neurological outcomes after perinatal hypoxia-ischemia.

scholarly journals Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex

2018 ◽  
Vol 29 (9) ◽  
pp. 3778-3795
Author(s):  
Alexandre Pons-Bennaceur ◽  
Vera Tsintsadze ◽  
Thi-thien Bui ◽  
Timur Tsintsadze ◽  
Marat Minlebaev ◽  
...  
Keyword(s):  
Human Population ◽  
Temporal Summation ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Treatment Strategies ◽  
Anticonvulsant Treatment ◽  
A1 Receptor ◽  
Adenosine Signaling

Abstract Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/−), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/− mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

scholarly journals Epileptiform Activity During Rewarming from Moderate Cerebral Hypothermia in the Near-Term Fetal Sheep

2005 ◽  
Vol 57 (3) ◽  
pp. 342-346 ◽  
Author(s):  
Luella C Gerrits ◽  
Malcolm R Battin ◽  
Laura Bennet ◽  
Hernan Gonzalez ◽  
Alistair J Gunn
Keyword(s):  
Epileptiform Activity ◽  
Fetal Sheep ◽  
Near Term

The pharmacology of endosomal TLR agonists in viral disease

2007 ◽  
Vol 35 (6) ◽  
pp. 1468-1472 ◽  
Author(s):  
D.R. Averett ◽  
S.P. Fletcher ◽  
W. Li ◽  
S.E. Webber ◽  
J.R. Appleman
Keyword(s):  
Viral Disease ◽  
Therapeutic Benefit ◽  
Innate Immune ◽  
Clinical Effects ◽  
Tlr Agonists ◽  
Tlr7 Agonist ◽  
Interferon Induction ◽  
Natural Ligands ◽  
Clinical Profiles

The discovery of endosomal TLRs (Toll-like receptors) and their natural ligands has accelerated efforts to exploit them for therapeutic benefit. Importantly, this was preceded by clinical exploration of agents now known to be endosomal TLR agonists. Clinical effects in viral disease have been reported with agonists of TLR3, TLR7, TLR7/8 and TLR9, and the TLR7 agonist imiquimod is marketed for topical use against warts, a papillomavirus disease. The observed pre-clinical and clinical profiles of agonists of each of these TLRs suggest induction of a multifaceted innate immune response, with biomarker signatures indicative of type 1 interferon induction. However, these agents differ in both their pharmaceutical characteristics and the cellular distribution of their target TLRs, suggesting that drugs directed to these targets will display differences in their overall pharmacological profiles.

scholarly journals Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kenta H. T. Cho ◽  
Nina Zeng ◽  
Praju V. Anekal ◽  
Bing Xu ◽  
Mhoyra Fraser
Keyword(s):  
Neurological Outcome ◽  
Fetal Sheep ◽  
Tlr7 Agonist

scholarly journals Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep

2019 ◽  
Vol 39 (4) ◽  
pp. 731-740 ◽  
Author(s):  
Ishmael M. Inocencio ◽  
Graeme R. Polglase ◽  
Suzanne L. Miller ◽  
Arvind Sehgal ◽  
Amy Sutherland ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Development ◽  
Growth Restriction ◽  
Limited Data ◽  
Artery Ligation ◽  
Fetal Sheep ◽  
Growth Status ◽  
Potent Vasodilator ◽  
And Function

Objective— The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results— Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions— SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

scholarly journals Non-Additive Effects of Delayed Connexin Hemichannel Blockade and Hypothermia after Cerebral Ischemia in Near-Term Fetal Sheep

2015 ◽  
Vol 35 (12) ◽  
pp. 2052-2061 ◽  
Author(s):  
Joanne O Davidson ◽  
Alexandra L Rout ◽  
Guido Wassink ◽  
Caroline A Yuill ◽  
Frank G Zhang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Activity ◽  
Recovery Period ◽  
Fetal Sheep ◽  
Treatment Groups ◽  
Intracerebroventricular Infusion ◽  
Eeg Power ◽  
Near Term ◽  
Connexin Hemichannel ◽  
Ischemic Encephalopathy

Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia ( n = 8), hypothermia for 3 days ( n = 8), connexin hemichannel blockade (50 umol/L intracerebroventricular over 1 hour followed by 50 umol/L over 24 hours, n = 8) or hypothermia plus hemichannel blockade ( n = 7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology ( P < 0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.

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