Minocycline improves the functional recovery after traumatic brain injury via inhibition of aquaporin-4

Abstract

Traumatic brain injury (TBI) is one of the main concerns worldwide as there is still no comprehensive therapeutic intervention. Astrocytic water channel aquaporin-4 (AQP-4) system is closely related to the brain edema, water transport at blood-brain barrier (BBB) and astrocyte function in the central nervous system (CNS). Minocycline, a broad-spectrum semisynthetic tetracycline antibiotic, has shown anti-inflammation, anti-apoptotic, vascular protection and neuroprotective effects on TBI models. Here, we tried to further explore the underlying mechanism of minocycline treatment for TBI, especially the relationship of minocycline and AQP4 during TBI treatment. In present study, we observed that minocycline efficaciously reduces the elevation of AQP4 in TBI mice. Furthermore, minocycline significantly reduced neuronal apoptosis, ameliorated brain edema and BBB disruption after TBI. In addition, the expressions of tight junction protein and astrocyte morphology alteration were optimized by minocycline administration. Similar results were found after treating with TGN-020 (an inhibitor of AQP4) in TBI mice. Moreover, these effects were reversed by cyanamide (CYA) treatment, which notably upregulated AQP4 expression level in vivo. In primary cultured astrocytes, small-interfering RNA (siRNA) AQP4 treatment prevented glutamate-induced astrocyte swelling. To sum up, our study suggests that minocycline improves the functional recovery of TBI through reducing AQP4 level to optimize BBB integrity and astrocyte function, and highlights that the AQP4 may be an important therapeutic target during minocycline treating for TBI.

Inhibition of aquaporin-4 and its subcellular localization attenuates below-level central neuropathic pain by regulating astrocyte activation in a rat spinal cord injury model

“…AQP4 is the most abundant water channel protein and is primarily responsible for water homeostasis of the CNS [ 66 ]. Several studies have reported that inhibition of AQP4 could significantly ameliorate edema and BBB disruption, reduce glial responses and neuronal apoptosis after CNS injury and neurodegenerative diseases [ 67 , 68 ]. AQP4 could also directly ameliorate severe atrophy and retrograde the degeneration of rubrospinal neurons after SCI [ 69 ].…”

Inhibition of NFAT5‐Dependent Astrocyte Swelling Alleviates Neuropathic Pain

“…[ 45 ] Increased AQP4 expression leading to excessive water influx is implicated in astrocyte swelling in pathological conditions such as cerebral edema and traumatic brain injury. [ 57 , 58 , 59 ] Thus, peripheral nerve injury may activate NFAT5‐AQP4 signaling, culminating in astrocyte swelling in the SDH.…”

Animal Models for Neuroinflammation and Potential Treatment Methods

“…Minocycline is known as a second-generation and semi-synthetic tetracycline antibiotic. Minocycline is quickly absorbed into the body, penetrates the BBB, and affects many biological actions (differing from its antibiotic action) both in vivo and in vitro , including the following: attenuation of BBB breakdown by inhibiting the production of matrix metalloproteinase-9; functional improvement after traumatic brain injury via suppression of aquaporin-4 production; relieve white matter injury in the neonatal rat brain by suppression of IL-1β and TNF-α production; neuroprotection from ischemic brain damage; alleviation of LPS-induced depressive-like behavior; and suppression of NOx production in cultured microglia under hypoxia ( 55 , 56 ). In our study, we demonstrated that intraperitoneal pretreatment with minocycline (20 mg/kg/day, 3 consecutive days) attenuated poly I:C-induced IL-1β mRNA expression in rat brain, transient fever, and decrease in locomotor activity ( 57 ).…”