Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance

Abstract

Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

“…Some evidence suggests that the effect of olanzapine under cytokine secretion is gender-dependent; female Sprague-Dawley rats given olanzapine (low dose 2 mg/day; high dose 4 mg/day) for 3 weeks showed increased IL-8 levels, while males showed TNF-α concentration during low dose consumption, proving a gender-dependent difference. Also, compared with those of the control group, IL-6 levels were reduced in males after both doses of olanzapine while IL-1β concentration was reduced in females after a low dose (208).…”

Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

“…Although we did not find a consistent trend of clozapine causing IL-6 and TNF-α changes in the peripheral blood of mice, we did find that the expression of IL-6 and TNF-α levels were increased in the pancreatic tissue of mice. Research has indicated that long-term olanzapine may induce glucose metabolic disorders by activating a peripheral inflammatory response, upregulating proinflammatory cytokines in plasma and adipose tissue (Li et al 2019). However, the impact of clozapine on proinflammatory cytokines in different tissues has received limited attention (Røge et al 2012).…”

Central Administration of Ampelopsin A Isolated from Vitis vinifera Ameliorates Cognitive and Memory Function in a Scopolamine-Induced Dementia Model

“…In addition, we found that chronic administration of ampelopsin A efficiently improved cognition and memory functions whereas acute administration of ampelopsin A did not improve these functions in the experimental animals (data not shown). Usually, chronic treatments were considered as over 10 days to 12 weeks [ 41 , 43 , 44 ], and similar central treatments for one month showed increases in memory functions [ 45 ]. To do so, chronic (a month) and low-dose treatments of ampelopsin A contribute to a change of cognitive and memory abilities.…”