Abstract
Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to evolution of neuronal injury. The present study investigated the neuroprotective effects and anti-inflammatory actions of berberine, an isoquinoline alkaloid, in both in vitro and in vivo TBI models. Mice subjected to controlled cortical impact injury were injected with berberine (10 mg·kg−1) or vehicle 10 min after injury. In addition to behavioral studies and histology analysis, blood-brain barrier (BBB) permeability and brain water content were determined. Expression of PI3K/Akt and Erk signaling and inflammatory mediators were also analyzed. The protective effect of berberine was also investigated in cultured neurons either subjected to stretch injury or exposed to conditioned media with activated microglia. Berberine significantly attenuated functional deficits and brain damage associated with TBI up to day 28 post-injury. Berberine also reduced neuronal death, apoptosis, BBB permeability, and brain edema at day 1 post-injury. These changes coincided with a marked reduction in leukocyte infiltration, microglial activation, matrix metalloproteinase-9 activity, and expression of inflammatory mediators. Berberine had no effect on Akt or Erk 1/2 phosphorylation. In mixed glial cultures, berberine reduced TLR4/MyD88/NF-κB signaling. Berberine also attenuated neuronal death induced by microglial conditioned media; however, it did not directly protect cultured neurons subjected to stretch injury. Moreover, administration of berberine at 3 h post-injury also reduced TBI-induced neuronal damage, apoptosis and inflammation in vivo. Berberine reduces TBI-induced brain damage by limiting the production of inflammatory mediators by glial cells, rather than by a direct neuroprotective effect.
Highlights
Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to neuronal injury and failure of functional recovery
Previous studies have shown that toll-like receptor 4 (TLR4)/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-kB (NF-kB) signaling mediates post-traumatic inflammatory responses and aggravates brain injury following TBI [19, 34]; we evaluated the effects of berberine on IL-1b-induced activation of TLR4-mediated pathways
This study showed for the first time that berberine administration reduced neuronal damage and cerebral edema and improved long-term functional recovery after TBI in mice
Summary
Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to neuronal injury and failure of functional recovery. Activated glia produce multiple pro-inflammatory mediators, including cytokines, chemokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Overproduction of these mediators is toxic to neighboring neurons, which further activates glial cells and injures the remaining neurons through positive feedback [1, 2]. Inhibition of glial activation and, production of inflammatory mediators may be a potential therapeutic strategy for protecting the damaged brain in TBI. A number of drugs targeting inflammatory pathways following TBI have been tested in clinical trials, none has conferred a significant benefit [5]
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