Tetramethylpyrazine reduces blood-brain barrier permeability associated with enhancement of peripheral cholinergic anti-inflammatory effects for treating traumatic brain injury

Abstract

Abstract. Traumatic brain injury (TBI) is a diverse group of intracranial injuries resulting from external mechanical insults to the brain. While basic and clinical research for TBI has been conducted for decades, it has not identified cost-effective medical interventions for treating TBI. Tetramethylpyrazine (TMP), which is derived from the Chinese herb, Ligusticum chuanxiong Hort (Chuan Xiong), has been clinically used for treating ischemic brain injury for years. However, whether TMP could provide effective benefits for improving the outcomes following TBI is unknown. In the present study, using controlled cortical impact (CCI) injury to create an animal model of TBI, the potential effects of TMP on improving blood-brain barrier (BBB) permeability in the early phase of the secondary injury, as well as the splenic anti-inflammatory activities, were evaluated. Cognitive functions were also assessed by Morris water maze trials following TBI. Results demonstrated that, at 24 h after CCI injury, BBB permeability was significantly reduced (P<0.05) by the application of TMP. In addition, within 24 h after CCI injury, the plasma levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and protein and mRNA expression levels of IL-1β and TNF-α in the spleen were significantly lowered by TMP (P<0.05). Furthermore, within 24 h after CCI injury, the activation of the splenic anti-inflammatory effects mediated by nicotinic acetylcholine receptor α7 (nAChRa7) stimulation were significantly enhanced by TMP (P<0.05). Additionally, impaired spatial memory acquisition and consolidation were significantly improved by TMP after CCI injury (P<0.05). Together, in light of these data, in the treatment of TBI, TMP could effectively reduce BBB permeability, which may be closely associated with the enhanced splenic anti-inflammatory effects activated by nAChRa7 stimulation, and potentially improve cognitive recovery concerning spatial learning and memory.

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“…Evidence from Shao et al demonstrated that LSZ protected neurons from apoptosis and death induced by oxygen-glucose deprivation [21]. Wang et al uncovered that LSZ played the anti-inflammatory activity in treating traumatic brain injury [22]. In addition, many reports considered that LSZ was an effective cure for the treatment of cancers.…”

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“…Tetramethylpyrazine (TMP) is an alkaloid found in the roots of Ligusticum chuanxiong Hort (Fig. 1) [18]. It has cardioprotective effects against myocardial IR injury: it limits infarct size and reduces apoptosis [19].…”

The Protective Effects and Potential Mechanisms of Ligusticum chuanxiong: Focus on Anti‐Inflammatory, Antioxidant, and Antiapoptotic Activities

“…In the progression of cerebral trauma, the permeability of the blood-brain barrier decreases due to the increase of TNF- α and IL-1 β . Wang et al reported that ligustrazine (20 mg/kg) can decrease the level of TNF- α and IL-1 β in the plasma of a rat model [ 63 ]. Additionally, through the NOS inhibition and the monoamine neurotransmitter modulation, senkyunolide I (16 and 32 mg/kg) showed treatment potential for migraine rats [ 64 ].…”