Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy

Abstract

Inflammation contributes to cognitive impairment in patients with hepatic encephalopathy (HE). However, the process by which peripheral inflammation results in cognitive impairment remains unclear. In animal models, neuroinflammation and altered neurotransmission mediate cognitive impairment. Taking into account these data, we hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering AMPA and/or NMDA receptors membrane expression; (3) reducing peripheral inflammation with infliximab (anti-TNF-a) would improve spatial learning; (4) this would be associated with reduced neuroinflammation and normalization of the membrane expression of glutamate receptors. The aims of this work were to assess these hypotheses. We analyzed in rats with portacaval shunt (PCS) and control rats, treated or not with infliximab: (a) peripheral inflammation by measuring prostaglandin E2, IL10, IL-17, and IL-6; (b) neuroinflammation in hippocampus by analyzing microglial activation and the content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; and (d) spatial learning in the Radial and Morris water mazes. We assessed the effects of treatment with infliximab on peripheral inflammation, on neuroinflammation and AMPA and NMDA receptors membrane expression in hippocampus and on spatial learning and memory. PCS rats show increased serum prostaglandin E2, IL-17, and IL-6 and reduced IL-10 levels, indicating increased peripheral inflammation. PCS rats also show microglial activation and increased nuclear NF-kB and expression of TNF-a and IL-1b in hippocampus. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory in the radial and Morris water maze. Treatment with infliximab reduces peripheral inflammation in PCS rats, normalizing prostaglandin E2, IL-17, IL-6, and IL-10 levels in serum. Infliximab also prevents neuroinflammation, reduces microglial activation, translocates NF-kB into nucleoli and normalizes TNF-a and IL-1b content in hippocampus. This was associated with normalization of AMPA receptors membrane expression in hippocampus and of spatial learning and memory. The results suggest that peripheral inflammation contributes to spatial learning impairment in PCS rats. Treatment with anti-TNF-a could be a new therapeutic approach to improve cognitive function in patients with HE.

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

“…Infliximab is an anti‐TNFα with high molecular mass. Therefore, the effects reported by Dadsetan et al must be because of the reduction of peripheral inflammation. These findings, summarized in Figure , support that in rats with hepatic encephalopathy, peripheral inflammation contributes to neuroinflammation in the hippocampus, which alters glutamatergic neurotransmission leading to spatial learning and memory impairment.…”

“…Neuroinflammation was associated with altered membrane expression of the GluA1 and GluA2 subunits of AMPA receptors and NR1 and NR2A subunits of NMDA receptors in the hippocampus and with impaired spatial memory and learning in the radial maze and Morris water maze. The PCS rats had more working and reference errors than control rats in the radial maze and showed impaired spatial memory in the Morris water maze …”

“…Dadsetan et al hypothesized that in rats with hepatic encephalopathy because of PCS, (a) peripheral inflammation is a main contributor to neuroinflammation; (b) neuroinflammation in the hippocampus alters glutamatergic neurotransmission by altering the membrane expression of AMPA and NMDA receptor subunits; (c) these alterations are responsible for impaired spatial learning and memory; (d) reduction of peripheral inflammation with infliximab (anti‐TNFα) would reduce neuroinflammation; (e) decreased neuroinflammation would normalize membrane expression of glutamate receptors; and (f) these alterations will improve spatial learning and memory.…”

“…Normalization of neurotransmission led to restoration of spatial learning and memory. Modified from Dadsetan et al…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…In addition, supplementation of CX3CR1-mediated signaling via soluble fractalkine infusion in the brain reduced microglia activation and neuroinlammation in AOM-treated mice [6]. TNFα-mediated signaling seems to play a signiicant role in neuroinlammation and outcomes during HE as inliximab, etanercept and p38 inhibitors all reduced serum and brain levels of proinlammatory cytokines and improved cognitive and motor functions in rodent models of HE [7,11,55].…”