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

Abstract

BackgroundLyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), affects both the central and peripheral nervous systems. Previously, we reported that in a model of acute LNB in rhesus monkeys, treatment with the anti-inflammatory drug dexamethasone significantly reduced both pleocytosis and levels of cerebrospinal fluid (CSF) immune mediators that were induced by Bb. Dexamethasone also inhibited the formation of inflammatory, neurodegenerative, and demyelinating lesions in the brain and spinal cord of these animals. In contrast, these signs were evident in the infected animals that were left untreated or in those that were treated with meloxicam, a non-steroidal anti-inflammatory drug.MethodsTo address the differential anti-inflammatory effects of dexamethasone and meloxicam in the central nervous system (CNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in culture supernatants of rhesus frontal cortex (FC) explants, primary rhesus astrocytes and microglia, and human oligodendrocytes. We also ascertained the potential of dexamethasone to modulate Bb-induced apoptosis in rhesus FC explants. As meloxicam is a known COX-2 inhibitor, we evaluated whether meloxicam altered the levels of COX-2 as induced by live Bb in cell lysates of primary rhesus astrocytes and microglia.ResultsDexamethasone but not meloxicam significantly reduced the levels of several Bb-induced immune mediators in culture supernatants of FC explants, astrocytes, microglia, and oligodendrocytes. Dexamethasone also had a protective effect on Bb-induced neuronal and oligodendrocyte apoptosis in rhesus FC explants. Further, meloxicam significantly reduced the levels of Bb-induced COX-2 in microglia, while both Bb and meloxicam were unable to alter the constitutive levels of COX-2 in astrocytes.ConclusionsThese data indicate that dexamethasone and meloxicam have differential anti-inflammatory effects on Bb-induced inflammation in glial and neuronal cells of the CNS and help explain the in vivo findings of significantly reduced inflammatory mediators in the CSF and lack of inflammatory neurodegenerative lesions in the brain and spinal cord of Bb-infected animals that were treated with dexamethasone but not meloxicam. Signaling cascades altered by dexamethasone could serve as possible therapeutic targets for limiting CNS inflammation and tissue damage in 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 . 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 . 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).…”

Metabolites of prostaglandin synthases as potential biomarkers of Lyme disease severity and symptom resolution

“…Microglial-culture studies consistently showed a significant upregulation of COX-2 expression in response to B. burgdorferi infection [25–28] with no change in COX-1 expression [26]. These effects may not be similar in astrocytes, where an increase in COX-2 mRNA in response to B. burgdorferi infection was observed in one study [27] but not in another [28].…”

“…Seven cell-culture studies were included in the present report, of which four investigated the effects of B. burgdorferi infection in brain microglial or astrocytic cells, two in joint cells, and one in splenic cells (Table 1 ). Microglial-culture studies consistently showed a significant upregulation of COX-2 expression in response to B. burgdorferi infection [ 25 – 28 ] with no change in COX-1 expression [ 26 ]. These effects may not be similar in astrocytes, where an increase in COX-2 mRNA in response to B. burgdorferi infection was observed in one study [ 27 ] but not in another [ 28 ].…”

“…Microglial-culture studies consistently showed a significant upregulation of COX-2 expression in response to B. burgdorferi infection [ 25 – 28 ] with no change in COX-1 expression [ 26 ]. These effects may not be similar in astrocytes, where an increase in COX-2 mRNA in response to B. burgdorferi infection was observed in one study [ 27 ] but not in another [ 28 ]. Treatment of B. burgdorferi -infected microglia with the NSAID Meloxicam reduced COX-2 activity but was unable to alter COX-2 activity in B. burgdorferi -infected astrocytes, suggesting that astrocytes may not respond to B. burgdorferi infection by upregulating COX-2 [ 28 ].…”