Comorbidity between epilepsy and depression: role of hippocampal interleukin-1beta.
Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however, its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1beta (IL-1beta) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1beta in epilepsy-associated depression and provide a rationale for the introduction of IL-1beta blockers in the treatment of depression in TLE.
Mazarati
Andrey M
AM
Department of Pediatrics, Neurology Division, D. Geffen School of Medicine at UCLA, 22-474 MDCC, Los Angeles, CA 90095-1752, USA. mazarati@ucla.edu
Pineda
Eduardo
E
Shin
Don
D
Tio
Delia
D
Taylor
Anna N
AN
Sankar
Raman
R
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015897:Comorbidity; D003292:Convulsants / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000150:complications* / Q000276:immunology / Q000503:physiopathology*; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D010862:Pilocarpine / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011903:Raphe Nuclei / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology
D000928:Antidepressive Agents; D003292:Convulsants; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D010862:Pilocarpine