Status Epilepticus: Stopping runaway seizures with a chill pill
The neuropeptide neurotensin can reduce status epilepticus and its associated consequences through induction of therapeutic hypothermia when bound to a molecule that can penetrate the blood-brain barrier.
- University of Iowa, Carver College of Medicine, United States
The brain consists of electrically excitable cells called neurons, which work in concert to regulate brain function. Sometimes, these cells become aberrantly connected and may activate together as a small network, leading to abnormal bursts of electrical activity known as seizures. Seizures disrupt the flow of messages between neurons and can lead to involuntary changes in behavior, sensation, and body movement or function.
Recurrent seizures are the hallmark of disease in patients with epilepsy (Langbein et al., 2024). Seizures that last a long time, also known as status epilepticus, can be life-threatening and require immediate treatment. Unfortunately, status epilepticus is often very difficult to control, leading to a high rate of morbidity and mortality (Kämppi et al., 2024).
Efforts to develop better therapies for status epilepticus are ongoing (O’Kula and Hill, 2024; Kishihara et al., 2024). One way to manage these kinds of seizures involves inducing hypothermia in the body and the brain to reduce cellular excitability (Kirmani et al., 2021). However, lowering body temperature using physical means, such as cooling blankets or infusions of cooled saline, can negatively affect the body. A more targeted way would be through medication that could pharmacologically alter body temperature.
While drugs targeting the biochemical pathways that regulate temperature homeostasis can lower body temperature, they often fail to reach the brain due to the blood-brain barrier, a protective semipermeable membrane between the blood and the brain. Thus, many drugs that lower body temperature do not markedly reduce brain temperature and have little to no effect on status epilepticus. Now, in eLife, Lotfi Ferhat, Michel Khrestchatisky and colleagues report a new approach to specifically reduce brain temperature and stop status epilepticus (Ferhat et al., 2024).
The researchers, who are based at various research institutes in France, targeted the biochemical pathway involving the signaling molecule neurotensin, which is known to regulate body temperature by lowering the set point on the thermostat that governs body temperature. As neurotensin cannot cross the blood-brain barrier, Ferhat et al. combined neurotensin with a molecule known to penetrate the brain and tested its effectiveness in mice. Specifically, these ‘conjugated’ versions were able to bind the low-density lipoprotein receptor (LDLR), which then transported the molecule across the blood-brain barrier intothe brain.
The researchers developed several conjugate proteins, and through a series of careful testing, identified one to employ throughout the study. The conjugate formed by this protein and neurotensin was successful in reaching the brain, inducing hypothermia, and reducing the seizures and cognitive and inflammatory changes associated with status epilepticus. However, it still needs to be confirmed that neurotensin-induced hypothermia alone is responsible for alleviating the effects associated with status epilepticus.
Regardless, the possibility of pharmacologically induced hypothermia for managing status epilepticus is exciting. Refractory status epilepticus (which continues despite treatment) is a dreadful condition with extremely high rates of mortality, despite the barrage of currently available therapies. Improved treatment modalities are sorely needed. While the findings of Ferhat et al. are promising, more needs to be learned about the safety of these treatments for the rest of the body. Such studies could be first trialled in animals but would later need to be replicated in humans. Moreover, while it is assumed that pharmacological means to induce hypothermia would have fewer negative consequences than physical means, this needs to be empirically evaluated. Hypothermia itself can have profound negative consequences, so the degree of hypothermia would need to be tightly monitored (Lu et al., 2024).
The extent of neuroprotection afforded by pharmacologically induced hypothermia could likely extend to other forms of neural injury, including stroke, post-anoxic brain injury or traumatic brain injury (Lin et al., 2024). Thus, implications for this promising work are potentially extremely far-reaching.
References
-
Mortality and morbidity of status epilepticus over the long termEpilepsy & Behavior 158:109918.https://doi.org/10.1016/j.yebeh.2024.109918
-
Super-refractory status epilepticus: prognosis and recent advances in managementAging and Disease 12:1097–1119.https://doi.org/10.14336/AD.2021.0302
-
Efficacy of second-line anticonvulsant agents with adult status epilepticus: A systematic review and network meta-analysisThe American Journal of Emergency Medicine 82:183–189.https://doi.org/10.1016/j.ajem.2024.06.019
-
Therapeutic approaches targeting seizure networksFrontiers in Network Physiology 4:1441983.https://doi.org/10.3389/fnetp.2024.1441983
-
Temperature control in acute brain injury: An updateSeminars in Neurology 44:308–323.https://doi.org/10.1055/s-0044-1785647
-
Severe hypothermia induces ferroptosis in cerebral cortical nerve cellsInternational Journal of Molecular Sciences 25:8086.https://doi.org/10.3390/ijms25158086
-
Improving quality of care for status epilepticus: Putting protocols into practiceCurrent Neurology and Neuroscience Reports 24:373–379.https://doi.org/10.1007/s11910-024-01356-9
Article and author information
Author details
Publication history
Copyright
© 2024, Buchanan
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 352
- views
-
- 33
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Status Epilepticus: Stopping runaway seizures with a chill pill
eLife 13:e102055.
https://doi.org/10.7554/eLife.102055
Further reading
-
- Computational and Systems Biology
- Neuroscience
Accumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here, we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions—the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS)—while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal’s choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.
-
- Neuroscience
Our propensity to materiality, which consists in using, making, creating, and passing on technologies, has enabled us to shape the physical world according to our ends. To explain this proclivity, scientists have calibrated their lens to either low-level skills such as motor cognition or high-level skills such as language or social cognition. Yet, little has been said about the intermediate-level cognitive processes that are directly involved in mastering this materiality, that is, technical cognition. We aim to focus on this intermediate level for providing new insights into the neurocognitive bases of human materiality. Here, we show that a technical-reasoning process might be specifically at work in physical problem-solving situations. We found via two distinct neuroimaging studies that the area PF (parietal F) within the left parietal lobe is central for this reasoning process in both tool-use and non-tool-use physical problem-solving and can work along with social-cognitive skills to resolve day-to-day interactions that combine social and physical constraints. Our results demonstrate the existence of a specific cognitive module in the human brain dedicated to materiality, which might be the supporting pillar allowing the accumulation of technical knowledge over generations. Intensifying research on technical cognition could nurture a comprehensive framework that has been missing in fields interested in how early and modern humans have been interacting with the physical world through technology, and how this interaction has shaped our history and culture.
