Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients

Abstract

Reports of cognitive decline, symptom worsening and brain atrophy in bipolar disorder (BD) suggest that the disease progresses over time. The worsening neuropathology may involve excitotoxicity and neuroinflammation. We determined protein and mRNA levels of excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. The brain tissue was matched for age, postmortem interval and pH. The results indicated statistically significant lower protein and mRNA levels of the N-methyl-Daspartate receptors, NR-1 and NR-3A, but significantly higher protein and mRNA levels of interleukin (IL)-1b, the IL-1 receptor (IL-1R), myeloid differentiation factor 88, nuclear factorkappa B subunits, and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) in postmortem frontal cortex from BD compared with control subjects. There was no significant difference in mRNA levels of tumor necrosis factor alpha or neuronal nitric oxide synthase in the same region. These data show the presence of excitotoxicity and neuroinflammation in BD frontal cortex, with particular activation of the IL-R cascade. The changes may account for reported evidence of disease progression in BD and be a target for future therapy.

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

“…The increased concentration of CSF IL-1β is in excellent agreement with a recent study showing increased mRNA levels of IL-1β in the postmortem brains of patients with bipolar disorder. 13 Given the similarities between schizophrenia and bipolar disorder, this finding is also in line with a recent study from our group showing increased concentration of this cytokine in the CSF of patients with a first-episode of schizophrenia. 2…”

“…The increased concentration of CSF IL-1β is in excellent agreement with a recent study showing increased mRNA levels of IL-1β in the postmortem brains of patients with bipolar disorder. 13 Given the similarities between schizophrenia and bipolar disorder, this finding is also in line with a recent study from our group showing increased concentration of this cytokine in the CSF of patients with a first-episode of schizophrenia. 2 The presently observed aberrant CSF cytokine profile in euthymic patients with bipolar disorder (i.e., a selective activation of IL-1β concomitant with a reduction of IL-6) clearly differs from previous findings where cytokines of serum have been analyzed.…”

“…8,17,18 Supporting a central origin of the presently observed increased IL-1β concentration, a recent postmortem study demonstrated higher protein and mRNA levels of IL-1β in patients with bipolar disorder. 13 However, since peripheral cyto kines may access the brain through a damaged blood-brain barrier or through volume diffusion where the barrier is absent, such as in paraventricular organs, a tentative contribution of peripheral cytokines to the brain in bipolar disorder should not be disregarded.…”

Neuroinflammation in bipolar disorders

“…This was due to the fact that our search strategy was over-inclusive to avoid missing any suitable article. [24] Germany [28] Neuroinflammatory microglia activation is compatible with these data; the influence of medication has not been ruled out *S100β induces the expression of IL-1β in cultured ratmicroglia; [37,38] astrocyte synthesis of S100β in AD may be triggered by microglial-derived IL-1. [39] BA: brodmann's area; TNFR2: tumor necrosis factor receptor, type 2; IL-1β: interleukin-1 beta; MIP 1α/LD78: macrophage inflammatory protein-1 alpha/LD78; PrP c : cellular prion protein; QRT-PCR: quantitative real-time polymerase chain reaction; MyD88: myeloid differentiation factor 88; NF-κB: nuclear factor kappa B; GFAP: glial fibrillary acidic protein; iNOS: inducible nitric oxide synthase; NMDA: N-methyl-D-aspartic acid; HERV: human endogenous retrovirus; HERV-W: human endogenous retrovirus-W; AA: arachidonic acid; cPLA2: cytosolic phospholipase A2; sPLA2-IIA: secretory phospholipase A2-IIA; COX: cyclooxygenase; mPGES: membrane prostaglandin E synthase; cPGES: cytosolic prostaglandin E synthase; TNF-α: tumor necrosis factor α It proved to be more tiresome to download all papers, but this allowed us to identify two papers that would otherwise have gone undetected.…”

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

“…It has been previously suggested that microglial cells might show reduced proliferation rates before BD onset, while cell degeneration might occur as a result of extensive inflammation due to microglia activation triggered by gliosis (Watkins et al, 2014). Additionally, histological brain analysis of frontal cortex samples showed an up-regulation of the pro-inflammatory and excitotoxicity-related proteins IL-1β, IL-1 receptor, iNOS and c-Fos suggesting that increased expression and activity rates of these might lead to cell death, brain atrophy and cognitive decline, as previously described for BD pathology (Rao et al, 2010). In the earlier stages of the disorder, interleukins and TNF-α are up-regulated while in later stages IL-6 and TNF-α levels expression are maintained (Rege and Hodgkinson, 2013).…”