A sterile animal model for neuroinflammation?

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Science Translational Medicine  18 Jan 2017:
Vol. 9, Issue 373, eaal4994
DOI: 10.1126/scitranslmed.aal4994


MRI-guided pulsed focused ultrasound combined with systemic infusion of contrast agent microbubbles induces local neuroinflammation in the rat.

Neuroinflammation has been postulated as a pathophysiological mechanism common to a number of brain diseases including Alzheimer’s disease and autism spectrum disorder. Animal models of neuroinflammation usually involve peripheral challenge with a noxious stimulus; for example, bacterial lipopolysaccharide, which activates microglia in the brain. Induction of neuroinflammation without systemic involvement has not been possible until recently. In a new study, Kovacs et al. report the induction of sterile inflammation in rat brain using MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of contrast agent microbubbles (MB). This methodology has been used to cause localized blood-brain barrier (BBB) disruption with the clinical goal of increasing drug or gene delivery for treating neurological diseases. Kovacs et al. demonstrated that pFUS+MB produced cavitation forces that resulted in shock waves that activated brain microglia, astrocytes, and neurons, in addition to the disruption of the BBB. They showed that this noninvasive, sterile method targeting the rat left cortex and striatum could trigger an immediate (within 5 min) damage-associated molecular pattern response (including an increase in heat-shock protein 70 and proinflammatory cytokines IL-1, IL-18, and TNFα), indicating a sterile inflammatory response (SIR) mediated by NFκB signaling in the rat brain parenchyma. This SIR response lasted for 12 to 24 hours. Furthermore, the authors reported release of cytokines, chemokines, trophic factors, and cell adhesion molecules, as well as injury of neurons and astrocytes after treatment of rats with pFUS+MB. Signs of neuroinflammation in the untreated contralateral hemisphere were absent.

MRI-guided pFUS+MB has the potential to become a new way to study neuroinflammation in the brain and its role in neurological and psychiatric diseases. Further studies to fine-tune precise targeting of specific brain structures will be needed. This is especially true for sub-cortical structures such as the amygdala and thalamus. Another question is the applicability of pFUS+MB for inducing neuroinflammation in other species such as mice and nonhuman primates. Much work will be needed to fully explore this new method for inducing sterile brain inflammation.

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