Authors :
Presenting Author: Teresa Ravizza, PhD – Mario Negri Institute for Pharmacological Research IRCCS
Akash Bera, BS – Mario Negri Institute for Pharmacological Research IRCCS
Sneha Anand, BS – Mario Negri Institute for Pharmacological Research IRCCS
Pasquale Baldassarre, undergraduate student – Mario Negri Institute for Pharmacological Research IRCCS
Rossella Di Sapia, PhD – Mario Negri Institute for Pharmacological Research IRCCS
Annamaria Vezzani, PhD – Mario Negri Institute for Pharmacological Research IRCCS
Rationale:
Recent studies have suggested the involvement of the gut-brain axis in the generation of seizures, but a causal link between the gut changes and epilepsy remains to be established. We found gut structural alterations and dysbiosis during development of acquired epilepsy in rodents. In particular, we found gut structural changes and inflammation associated with a reduction in the abundance of bacteria producing short chain fatty acids (SCFAs) by fermentation of dietary fibres. Since SCFAs mediate anti-inflammatory and anti-oxidant effects in the gut and brain, their reduced production may contribute to exacerbation of inflammation and oxidative stress, two phenomena implicated in epilepsy. We studied whether SCFAs administered to mice developing epilepsy reduce seizures, neuropathology and cognitive deficits, and prevent gut modifications that occur during epileptogenesis. Methods:
Epilepsy was induced by intra-amygdala kainate to provoke status epilepticus (SE) followed by epilepsy development in C57Bl6 adult male mice. Mice develop drug-resistant seizures, neuropathology, cognitive deficits, and gut dysbiosis/dysfunction. After SE, mice were randomized to a combination of SCFAs (40 mM sodium butyrate, 26 mM sodium propionate, 67 mM sodium acetate) added to drinking water or a vehicle solution (133 mM NaCl) (n= 10-12/group) for the duration of the experiment. Sham mice were injected intra-amygdala with saline and similarly treated (n=8/each group). EEG monitoring was done continuously (24/7) from SE onset for 10 weeks to quantify seizure, then mice were tested for cognitive deficits in the Barnes Maze. At the end of the experiment, mice were killed and their brain and gut tissues were processed by immunohistochemistry, and blood collected for SCFAs measurements.Results:
SCFAs treatment reduced both the number of mice showing seizure progression during 10 weeks and the seizure progression index (number of seizures during weeks 6-10 vs weeks 1-5) compared to vehicle mice (p< 0.05). SCFAs also reduced (p< 0.05) the number of mice with seizure clusters (≥3 seizures/24h). SCFAs-treated SE mice showed improvement in memory retention and escape hole search strategy during the probe trial (24h after completing learning trials) compared to vehicle mice (p< 0.05). T