Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

Abstract

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.

On the Digital Psychopharmacology of Valproic Acid in Mice

“…Thus, rather than aim for a specific plasma or brain concentration, we began by exploring the effects of VPA dissolved in drinking water (o.s.) at a dose range of ∼500-600 mg/kg/d, previously demonstrated to provide some seizure protection in rodent models (Frisch et al, 2009;Smeland et al, 2012;De Caro et al, 2019;Citraro et al, 2020). Eight to nine weeks old C57BL/6J mice were admitted to BMU home-cage chambers fitted with a single lickometered water source (0.8% sucrose drinking water), an infrared-lucent shelter and food hopper (fitted to sense beam breaks).…”

“…In this study, we apply instrumented home-cage monitoring (Loos et al, 201 015;Robinson et al, 2018;Jankovic et al, 2019) to non-invasively and unobtrusively assess the psychopharmacology of adult and prenatal VPA exposure in C57BL/6J mice. As opposed to VPA injections applied during specific gestational windows (Roullet et al, 2013;Nicolini and Fahnestock, 2018) or administered acutely to demonstrate acute seizure protection (Nau and Loscher, 1982;Watanabe et al, 2010), we apply VPA enterally, dissolved in drinking water (Loscher and Nau, 1982;Frisch et al, 2009;Smeland et al, 2012;De Caro et al, 2019;Citraro et al, 2020). By combining undisturbed recordings of spontaneous behavior with carefully selected provocative maneuvers, we illustrate an ethologically sound approach to ascertain drug-induced changes in specific behavioral domains (e.g., feeding, sheltering, etc.)…”

The comorbidities of epilepsy explained

“…Reciprocal comorbidities include a number of conditions characterized by the so-called 'bidirectional relationship' meaning that not just the epilepsy is associated with an increased risk of developing these disorders but also these disorders are associated with an increased risk of developing epilepsy. This phenomenon has been historically described for many psychiatric comorbidities including mood and anxiety disorders, psychoses and schizophrenia, attention deficit hyperactivity disorder (ADHD) and autism [7] but more recently the same phenomenon has been described for medical conditions such as type 1 diabetes, irritable bowel syndrome, and autoimmune disorders [9]. Mechanisms linking reciprocal comorbidities are complex, multifactorial, and likely to be different from condition to condition.…”

On the Digital Psychopharmacology of Valproic Acid in Mice

“…Thus, rather than aim for a specific plasma or brain concentration, we began by exploring the effects of VPA dissolved in drinking water (o.s.) at a dose range of ~500-600mg/kg/d, previously demonstrated to provide some seizure protection in rodent models [35][36][37][38] . 8-9week old C57BL/6J mice were admitted to BMU home-cage chambers fitted with a single lickometered water source (0.8% sucrose drinking water), an infrared-lucent shelter and food hopper (fitted to sense beam breaks).…”

“…In this study, we apply instrumented home-cage monitoring 32 to noninvasively and unobtrusively assess the psychopharmacology of adult and prenatal VPA exposure in C57BL/6J mice. As opposed to VPA injections applied during specific gestational windows 25,26 or administered acutely to demonstrate acute seizure protection 33,34 , we apply VPA enterally, dissolved in drinking water [35][36][37][38][39] . By combining undisturbed recordings of spontaneous behavior with standardized provocative maneuvers, we illustrate an ethologically sound approach to ascertain drug-induced changes in specific domains of behavior (e.g., feeding, sheltering, etc.)…”