Abstract

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24–71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.

Highlights

  • We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure

  • We have previously shown that this same 3X exposure regimen caused acute BBB disruption, which was closely associated with later emerging chronic neuron loss in the cerebellum[11]

  • Monocyte (CD11b+, CD45 high) infiltration, which was not significantly affected by blast exposure in either the cerebellum (F(2,24) = 0.081, n.s.) or forebrain (F(2,24) = 0.902, n.s.). These results demonstrate that repetitive blast exposure induces brain region-specific, NOS-dependent, CD4+ T-cell infiltration that corresponds to the differential effects of blast on BBB integrity in the cerebellum versus forebrain regions

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Summary

Introduction

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. We and others have shown that blast exposure causes transient BBB disruption[8,10,26], suggesting that blast stimulates short-term neurovascular repair processes that interact with more protracted, co-occurring, pathological cascades that undermine BBB integrity In this regard, blast has been shown to provoke delayed-onset BBB disruption, days after an initial BBB opening was restored to normal[8].

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