Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats.

Nikolett Szarka,Istvan Hernadi,Sai Ambika Tadepalli,Zsolt Kristof Bali,Matyas Wahr,Zoltan Ungvari,Akos Koller,Andras Czigler,Zoltan Kellermayer,Andras Buki,Krisztina Amrein,Endre Czeiter,Peter Toth,Luca Toth

doi:10.3390/ijms20133223

Abstract

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Highlights

Traumatic brain injury (TBI) is a serious health problem worldwide resulting in significant chronic disabilities
We found that Mild TBI (mTBI) led to a significant disruption of the blood-brain barrier detected two weeks after mTBI in hypertensive rats (n = 7), as shown by increased Evans blue content of cerebral tissue of these animals
We found that two weeks after mild TBI fibrin accumulated in cortical tissue of hypertensive rats (n = 6), which could not be observed in spontaneously hypertensive rats (SHR) without mTBI (n = 6) or normotensive rats with and without mTBI (n = 6, in both groups) (Figure 1C)

Summary

Introduction

Traumatic brain injury (TBI) is a serious health problem worldwide resulting in significant chronic disabilities. After the mechanical force-induced primary brain injury, TBI initiates a variety of pathophysiological processes leading to secondary brain damage [1,2,3], which contributes to the development of long-term psychiatric problems and cognitive decline [2]. Disruption of the blood-brain barrier plays a central role in the secondary pathological processes (reviewed in [4]), leading to accumulation of blood-borne substances in the cerebral parenchyma, neuroinflammation and consequent decline in higher brain function. In the present study we tested the hypothesis that mild TBI induces persistent, long term disruption of the BBB in hypertensive rats, leading to persistent accumulation of blood borne substances in the brain parenchyma, neuroinflammation and cognitive decline

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