Anti-inflammatory effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in neuronal cultures of dorsal root ganglia and myelinating cells of the peripheral nervous system

Abstract

BackgroundLyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), could result in cognitive impairment, motor dysfunction, and radiculoneuritis. We hypothesized that inflammation is a key factor in LNB pathogenesis and recently evaluated the effects of dexamethasone, a steroidal anti-inflammatory drug, and meloxicam a non-steroidal anti-inflammatory drug (NSAID), in a rhesus monkey model of acute LNB. Dexamethasone treatment significantly reduced the levels of immune mediators, and prevented inflammatory and/or neurodegenerative lesions in the central and peripheral nervous systems, and apoptosis in the dorsal root ganglia (DRG). However, infected animals treated with meloxicam showed levels of inflammatory mediators, inflammatory lesions, and DRG cell apoptosis that were similar to that of the infected animals that were left untreated.MethodsTo address the differential anti-inflammatory effects of dexamethasone and meloxicam on neuronal and myelinating cells of the peripheral nervous system (PNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in rhesus DRG cell cultures and primary human Schwann cells (HSC), using multiplex enzyme-linked immunosorbent assays (ELISA). We also ascertained the ability of these drugs to modulate cell death as induced by live Bb in HSC using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay and the potential of dexamethasone to modulate Bb-induced apoptosis in HSC by the TUNEL assay.ResultsEarlier, we reported that dexamethasone significantly reduced Bb-induced immune mediators and apoptosis in rhesus DRG cell cultures. Here, we report that dexamethasone but not meloxicam significantly reduces the levels of several cytokines and chemokines as induced by live Bb, in HSC and DRG cell cultures. Further, meloxicam does not significantly alter Bb-induced cell death in HSC, while dexamethasone protects HSC against Bb-induced cell death.ConclusionsThese data help further explain our in vivo findings of significantly reduced levels of inflammatory mediators, DRG-apoptosis, and lack of inflammatory neurodegenerative lesions in the nerve roots and DRG of Bb-infected animals that were treated with dexamethasone, but not meloxicam. Evaluating the role of the signaling mechanisms that contribute to the anti-inflammatory potential of dexamethasone in the context of LNB could serve to identify therapeutic targets for limiting radiculitis and axonal degeneration in peripheral LNB.

Borrelia burgdorferi Infection and Lyme Disease in North American Horses: A Consensus Statement

“…The use of NSAIDs in horses with pain or neurologic signs suspected to be because of Lyme disease remains common practice but evidence of efficacy is lacking. In vivo experimental studies in rhesus monkeys have shown that meloxicam does not decrease levels of inflammatory mediators, dorsal root ganglia‐apoptosis, and inflammatory neurodegenerative lesions in the nerve roots and dorsal root ganglia of B. burgdorferi ‐infected cells . Dexamethasone treatment in humans with B. burdorferi infection has likely been associated with both beneficial and harmful outcomes, with worse long‐term outcomes reported in one study .…”

“…In vivo experimental studies in rhesus monkeys have shown that meloxicam does not decrease levels of inflammatory mediators, dorsal root ganglia-apoptosis, and inflammatory neurodegenerative lesions in the nerve roots and dorsal root ganglia of B. burgdorferi-infected cells. 109,110 Dexamethasone treatment in humans with B. burdorferi infection has likely been associated with both beneficial and harmful outcomes, 110 with worse long-term outcomes reported in one study. 111 Although clinical signs could improve transiently, the committee does not recommend corticosteroids for equine Lyme disease except in some cases of uveitis or neuroborreliosis that are both acute and severe (Level 2).…”

Effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in glial and neuronal cells of the central nervous system

“…Further, meloxicam was able to significantly reduce the levels of Bb-induced COX-2 in rhesus microglia, while it did not alter the constitutive levels of COX-2 in rhesus astrocytes. These data indicate that as with PNS cells [ 13 ], dexamethasone and meloxicam have differential anti-inflammatory effects on Bb-induced inflammation in glial and neuronal cells of the CNS.…”

Spirochetal Lipoproteins and Immune Evasion

“…One of the primary manifestations of spirochetal infection is tissue inflammation that is the mainstay of spirochetal diseases such as Lyme neuroborreliosis (22, 29). Spirochetal lipoproteins are known to induce strong pro-inflammatory responses in their hosts (27, 33, 34, 44–52) that comprise the initial innate immune response to the invading pathogen (49).…”

“…Spirochetal membranes play a pivotal role in interacting with a host’s immune system (19, 20). Bacterial components such as lipopolysaccharides (LPSs) often play a major role in the induction of inflammation in bacterial infections (21, 22). Interestingly, aggressive immune responses are often observed despite the lack of LPS (endotoxin) in particular spirochetes, such as Borrelia burgdorferi (19, 23–25).…”