Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Abstract

A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1β, TNF-α and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1β, TNF-α, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1β was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-α was expressed to a lesser extent than IL-1 β, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrates the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.

Oxidative damage is present in the fatal brain edema of diabetic ketoacidosis

“…The expression of HO-1 in the hippocampus of the DKA/BE cases is in keeping with the expression of the protective molecules HSP70 and IL-10 in these cases (Hoffman et al, 2007), as well as their increased systemic expression prior to treatment of severe DKA (Oglesbee et al, 2005) (Hoffman et al, 2003a). …”

“…The inverse relation between insulin and IGF-1 receptors with neuronal density in the cerebellum (Hoffman et al, 2010), and the selective neuronal adaptation of the cerebellum to chronic sublethal oxidative stress provided by altered cholesterol and sphingolipid (Clement et al, 2009), are possible explanations for the limited insult of oxidative stress in the cerebellum. Neither 8OHG, HO-1 nor HNE were consistently expressed in the epithelial cells of the choroid plexus, in contrast to the expression of NT (Hoffman et al, 2009; Hoffman et al, 2010) and the neuroinflammatory response, including RAGE, in the choroid plexus of the DKA/BE cases (Hoffman et al, 2007; Hoffman et al, 2008) This suggests that the choroid plexus selectively compensates for the oxidative stress of DKA/BE (Skinner et al, 2006; Hoffman et al, 2007; Marques et al, 2009)…”

Autophagy in the brains of young patients with poorly controlled T1DM and fatal diabetic ketoacidosis

“…This stress results in the gradual impairment of neuronal function, decreased production of ATP, and possible cell death (Terman et al, 2007). It is important to recognize that HSP70, a stabilizer of protein metabolism, is diffusely expressed in DKA/BE (Hoffman et al, 2007) and is increased systemically prior to treatment of severe uncomplicated (without BE) DKA (Oglesbee et al, 2005). Thus HSP70 could provide protection against the oxidative stress during normal metabolism and lysosomal membrane permeabilization (Nylandsted et al, 2004) such as occurs in retinal pigment epithelial cells in macular degeneration (Kaamiranta et al, 2009).…”

Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

“…Accumulation of oxidative mediators, cytokines or matrix metalloproteinase MMP-9 are some of the factors that may be involved in BBB disruption in these conditions [72,76]. …”