Diet After Status Epilepticus: Keto Reduces Inflammation and Repairs Axonal Wiring

In Pediatric Discovery, they showed that a classic ketogenic diet (high fat, low carbohydrate) helps rats with status epilepticus to “reassemble” their memory faster and heal the neural networks of the hippocampus. At the molecular level, the diet dampened the NF-κB inflammatory pathway and reduced levels of proinflammatory cytokines. The work is preclinical (a model on young rats), but it provides a mechanistic clue as to why keto approaches sometimes improve cognitive symptoms in people with epilepsy.

Background of the study

• Problem after a severe attack. Even when the seizures are stopped, children and adolescents often have memory and attention deficits after status epilepticus - the hippocampus suffers especially.
• What is already being done. The ketogenic diet (KD) has long been used for drug-resistant epilepsy: in some patients, it reduces the frequency of seizures. But it is much less well understood whether KD helps restore cognitive functions after severe seizures and due to what.
• Suspected mechanism: One of the main “amplifiers” of damage after status is neuroinflammation. The central switch of this process is the NF-κB pathway; its activation is associated with neuronal death, myelin damage, and the “disintegration” of neural networks in the hippocampus.
• The main gap. There was a lot of data that KD changes energy metabolism (ketones, mitochondria) and reduces seizure readiness, but there is no direct evidence that it:
  1. dampens NF-κB inflammation after status and
  2. improves memory in parallel with the restoration of "wiring" (myelin/axonal markers),
     which was lacking, especially in the juvenile model, relevant to pediatrics.
• Why adolescent rats? Children's brains are still developing, and the effects of status may differ from those in adults. The juvenile rat model allows us to simulate the childhood context and track how diet affects network recovery during this sensitive period.
• What the authors wanted to check. Will a short course of KD give after the status:
  • improving spatial and working memory,
  • signs of remyelination/reaxon recovery in the hippocampus,
  • and a reduction in NF-κB and proinflammatory cytokine activity—that is, whether the behavioral benefit is associated with an anti-inflammatory effect.
• Practical meaning. If the link “KD → less NF-κB → better memory” is confirmed in humans, this will strengthen the position of KD not only as an anticonvulsant measure, but also as an element of rehabilitation of the cognitive consequences of severe seizures (under medical supervision, of course).

What did you do?

• The pilocarpine model of status epilepticus, a severe, prolonged seizure that often results in memory loss, was reproduced in young rats (21 days of life). The animals were then divided into groups and transferred to either a ketogenic diet (KD) or a normal diet for 7 or 20 days.
• Behavior and memory were tested: Morris maze (spatial learning), Y-maze (working memory), novel object recognition, raised cross (anxiety/exploratory behavior). In parallel, the brain was studied: immunohistochemistry and Western blot for markers of neural networks (NeuN), myelin (MBP), axons (NF200), and NF-κB pathway activity (p65, p-IκB). From the blood - ketones and weight.

What did you find?

• Memory improved. After 7-20 days on keto, rats were better able to navigate in water, more often “guessed” new things, and behaved more smoothly in working memory tests. That is, cognitive lapses after status epilepticus became noticeably smaller.
• The wiring in the hippocampus was restored. In the context of KD, the hippocampus showed increased levels of myelin (MBP) and axonal markers (NF200), and the number of mature neurons (NeuN+) in vulnerable areas looked better – biological clues to behavioral improvements.
• The inflammation subsided. The diet reduced the nuclear localization of NF-κB p65, decreased the p-IκB/IκB ratio and the levels of TNF-α, IL-6, IL-1β — signals that neuroinflammation is really dying down. In control (healthy) rats, KD did not produce such shifts — the effect manifested itself precisely after the attack.
• Metabolism “switched”. On KD, ketone bodies naturally increased; body weight behaved differently, but critically, the cognitive benefit went hand in hand with a decrease in inflammatory markers.

Why is this important?

Epilepsy is not just about seizures. Some children and adults still have problems with memory and attention even when seizures are controlled. The keto diet has long been used as a treatment for drug-resistant epilepsy, but the mechanism for cognitive benefit has been unclear. Here, a plausible “bridge” is shown: ketones → inhibition of NF-κB → fewer cytokines → less damage to neural networks → better memory. PMC

What does this mean for people?

• The study is on rats. It doesn't prove that every child/adult after a severe attack urgently needs a keto diet. But it does support the idea that part of the cognitive benefit of keto approaches may come from an anti-drilling effect on neuroinflammation.
• Keto is a medical diet, especially in pediatrics: it is prescribed and administered by a neurologist and nutritionist, monitoring lipids, microelements, gastrointestinal tolerance, growth, etc. Self-medication is not necessary here.
• In real-life practice, diet is often chosen when two or more anticonvulsant drugs have failed; new data strengthen the motivation to monitor cognitive effects as well as seizure frequency.

Where are the restrictions and what next?

• The model is pilocarpine and juvenile; transfer to other forms of epilepsy and to humans requires separate testing.
• The authors did not pharmacologically tweak the NF-κB pathway itself (there are no experiments to turn the pathway on/off while on a diet), so the causality is still indirect. They write directly that the next step is to combine KD with NF-κB modifiers and see if this axis is necessary for cognitive benefit.
• Also not explored are the alternative mechanisms of keto: mitochondria, oxidative stress, GABA/glutamate - they probably add their contribution.

What do the authors consider to be the most important thing?

• The keto diet shift. It’s not just about reducing seizure activity: in a model of post-status epilepticus, the ketogenic diet is associated with improved memory and less hippocampal damage, which goes hand in hand with dampening the NF-κB pathway and pro-inflammatory cytokines. That is, metabolic intervention may work as a “repair” element in the brain. PMC
• Mechanistic bridge. They see a plausible chain: “ketones → ↓NF-κB → ↓IL-1β/IL-6/TNF-α → better neural networks and myelin → better cognition.” This explains why some patients on keto not only experience improvement in seizures but also in cognitive symptoms.

What do the authors warn about?

• This is preclinical. The results were obtained on juvenile rats in the pilocarpine model. Transfer to humans requires clinical trials; the keto diet in real practice is a medical therapy, not a DIY experiment.
• The causality of NF-κB still needs to be “bolted down”. Path has not been “twisted” separately pharmacologically/genetically. The next step is to combine keto with NF-κB modulators to confirm that this axis is critical for cognitive benefit.

Where are they looking next?

• To the clinic - carefully and according to the protocol. Check what duration and window of the start of the diet is better after a severe attack, how long the effect lasts and for whom it is especially useful (for example, children with drug-resistant epilepsy).
• Combination strategies. The authors suggest thinking about the synergy of metabolic and molecular interventions: diet + targeting inflammation/stress — to treat both seizures and the “silent” damage from them.

In short: the team emphasizes that the keto diet in their model appears to be a tool for restoring neural networks after status - but emphasizes the limits of extrapolation and the need for clinical trials before making recommendations to people.

Conclusion

After severe status epilepticus, the brain needs a quiet environment to recover. The keto diet in a rat model does just that: it switches metabolism to ketones and silences the inflammatory loudspeaker NF-κB, which coincides with improved memory and hippocampal wiring. Clinical trials are still in the works before recommendations to patients can be made, but the mechanistic path has become clearer.

Study source: W. Wang et al. Protective Effects of the Ketogenic Diet on Cognitive Impairment Induced by Status Epilepticus in Rats: Modulation of Neuroinflammation Through the NF-κB Signaling Pathway. Pediatric Discovery, 23 Jun 2025, 3(2):e70013. https://doi.org/10.1002/pdi3.70013