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Compositions and methods for inhibiting seizures

A composition and food technology, applied in the direction of drug combination, medical preparation containing active ingredients, drug delivery, etc., can solve the problems of insufficient understanding, lack of molecular and/or cellular targets, etc.

Pending Publication Date: 2019-10-11
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, the mechanisms underlying the beneficial effects of KD are poorly understood and molecular and / or cellular targets for intervention are lacking

Method used

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  • Compositions and methods for inhibiting seizures
  • Compositions and methods for inhibiting seizures
  • Compositions and methods for inhibiting seizures

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Materials and methods

[0057] animals and meals

[0058]3- to 4-week-old SPF wild-type Swiss Webster mice (Taconic Farms), GF wild-type Swiss Webster mice (Taconic Farms), and SPF C3HeB / FeJ KCNA1 KO mice (Jackson Laboratories) were housed in the UCLA Health Sciences Center Barrier Facility . Breeding animals were fed "Breeders" diet (Lab Diets 5K52). Experimental animals were fed standard chow (Lab Diet 5010), a 6:1 ketogenic diet (Harlan Teklad TD.07797.PWD) or a vitamin and mineral matched control diet (Harlan Teklad TD.150300). Juvenile mice were used to i) mimic the typical use of KD to treat pediatric and juvenile epilepsy patients, and ii) align the timing of mouse brain development with early human brain development, where neurodevelopment in the case of 3-week-old mice Important events are similar to neurodevelopmental important events in the 2-3 year old human brain 60 , and iii) exclude pre-weaning dietary treatments where the effect of the d...

Embodiment 2

[0097] Example 2: Ketogenic Diet Alters Gut Microbiota and Confers Protection Against Seizures

[0098] A 6 Hz psychomotor seizure model of treatment-resistant epilepsy involves low-frequency corneal stimulation to induce focal cognitively impaired seizures suggestive of human temporal lobe epilepsy. KD protected against 6 Hz seizures, as indicated by an increase in the current intensity (CC50, seizure threshold) required to induce seizures in 50% of test subjects. Specific pathogen free (SPF) Swiss Webster mice were fed a 6:1 fat:protein KD or a vitamin and mineral matched control diet (CD). Mice fed KD exhibited an elevated seizure threshold in response to 6 Hz stimulation compared to CD controls ( Figure 1A ), decreased serum glucose ( Figure 1B ) and serum β-hydroxybutyrate (BHB; Figure 1C )Increase. There were no significant differences in food consumption or weight gain between the CD group versus the KD group.

[0099] In addition to raising the seizure thresh...

Embodiment 3

[0100] Example 3: Gut microbiota confers an anti-seizure effect on a ketogenic diet

[0101] The 6 Hz psychomotor seizure threshold was measured in germ-free (GF) and antibiotic-treated (Abx)-treated SPF mice to determine whether the gut microbiota is required for the anti-seizure effects of a ketogenic diet.

[0102] SPF mice fed KD for 14 days (SPF KD) exhibited increased seizure threshold and altered microbiota compared to CD controls (SPF CD) ( Figure 3A and Figure 1D ). This was abolished in GF mice (Fig. 3A) and Abx-treated SPF mice (Fig. 3C), indicating that the gut microbiota is required for KD-mediated increased seizure protection. Normalization of GF mice with SPF gut microbiota restored KD-associated seizure protection to levels seen in the context of native SPF KD mice (Fig. 3A), suggesting a role for the microbiome in KD seizure resistance The mediation was not dependent on pre-weaning microbiota colonization, and the microbiota actively mediated the seizur...

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Abstract

Provided herein are methods and compositions related to treating or preventing seizures. In some aspects, provided herein are methods of treating or preventing seizures in a subject by administering to the subject a composition comprising Parabacteroides and Akkermansia bacteria.

Description

[0001] related application [0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 436,711, filed December 20, 2016, and U.S. Provisional Patent Application Serial No. 62 / 447,992, filed January 19, 2017, each of which Incorporated herein by reference in its entirety. [0003] Government funding [0004] This invention was made with government support under Grant No. GM065823 and Grant No. GM106996 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Epilepsy is characterized by recurrent seizures that can lead to loss of consciousness, loss of perception and / or disturbance of movement, autonomic function, sensation (including vision, hearing and taste), mood and / or mental function. Epilepsy afflicts 1-2% of the population in developed countries. [0006] A low-carbohydrate high-fat ketogenic diet (KD) is a treatment for refractory epilepsy in wh...

Claims

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Application Information

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IPC IPC(8): A61K35/741A61P25/08A61P25/16A61P25/28
CPCA61K35/741A61P25/08A23L33/30A23L33/135A61P25/00A61K9/0031A61K9/0053A61K35/74A61K2035/115A61K39/0216
Inventor E·萧J·矢野H·王C·奥尔森
Owner RGT UNIV OF CALIFORNIA
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