Blocking Borrelia in the brain

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Science Translational Medicine  03 Feb 2016:
Vol. 8, Issue 324, pp. 324ec18
DOI: 10.1126/scitranslmed.aaf2005

Lyme disease, the most common tick-borne infection, is caused by Borrelia spirochetes that are transmitted to humans by ticks of the genus Ixodes. Since it was first described in 1975, the number of reported cases in the US has been rising, and the CDC estimates an incidence of 300,000 per year. Neuroborreliosis is a rare but potentially serious complication that occurs in up to 15% of untreated patients with Lyme disease, often affecting both the central and peripheral nervous systems. Common presentations include aseptic meningitis and facial palsy, which are treated effectively with antibiotic therapy. However, permanent neurological injury can occur as a result of the inflammatory response if treatment is delayed. In prior work, Martinez et al. showed that Borrelia induces numerous inflammatory mediators in the nonhuman primate brain, which leads to apoptosis of oligodendrocytes and neurons. Now they confirm that the inflammation in neuroborreliosis is mediated in part by the neuropeptide Substance P (SP) and its high-affinity neurokinin-1 receptor (NK1R) and can be blocked by a specific NK1R antagonist. Using primary explant cultures from nonhuman primate brain and dorsal root ganglia, Martinez et al. found that pretreatment with compound L703,606 significantly decreased proinflammatory cytokines (IL-6, IL-8, CCL2), as well as decreased apoptosis. This work in a nonhuman primate model extends prior work in murine models which showed that SP/NK1R interactions are required in vivo for inflammation after challenge with B. burgdorferi. Meanwhile, NK1R knockout mice show reduced brain injury (gliosis, demyelination, cytokine elevation) after infection with Borrelia.

SP is found in multiple regions of the human brain and spinal cord, including the cortex, hippocampus, basal ganglia, and brainstem. In addition to their presence in neurons, SP and its cognate receptors are also present in microglia, endothelial cells, and peripheral immune cells. NK1R is a G protein–coupled receptor with diverse downstream pathways, which vary depending upon the cell type. As one might expect from its wide anatomical distribution and expression, SP/NK1R is involved in a variety of complex physiological responses including pain, emotion, neuroinflammation, and microvascular permeability. In response to Borrelia infection, SP activates microglia and astrocytes through COX2 to produce PGE2 and potentiates the glial cytokine response. It is therefore noteworthy that in related in vivo work, Martinez et al. showed that treatment with dexamethasone, but not with a COX2 inhibitor, abrogated the inflammatory response to neuroborreliosis in nonhuman primates. This is important because steroids not only modulate the inflammatory cytokine response but also limit permeability at the blood-brain barrier, which could help to counteract SP-induced vascular leakiness in the setting of neuroborreliosis. Rapid administration of steroids for fulminant meningitis is already established clinical practice for both children and adults, but the potential benefits of either dexamethasone or NK1R antagonists remain to be proven in human neuroborreliosis where the typical clinical course is more indolent. NK1R antagonists are currently under investigation and show promise for neuroinfectious disease applications. At this time, the only FDA-approved NK1R antagonist drugs are used for treating symptoms of chemotherapy-induced nausea and emesis, but there is interest in testing this class of drugs for a number of other conditions including neurodegenerative diseases, depression, and cerebral edema following stroke or traumatic brain injury.

A. N. Martinez et al., Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis. J. Neuroinflammation 10.1186/s12974-015-0453-y (2015). [Full Text]

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