Departments of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto, Kumamoto, Japan; Department of Pharmaceutical Science, School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1, Enokizu, Okawa, Fukuoka 8318501, Japan.
Departments of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto, Kumamoto, Japan.
Exp Gerontol. 2021 May;147:111286. doi: 10.1016/j.exger.2021.111286. Epub 2021 Feb 17.
Brain-derived neurotrophic factor (BDNF) is known to have neuroprotective effects on multiple neurovascular diseases especially poststroke recovery. On the other hand, BDNF reported to increase blood pressure (BP) which is one of the major risk factors for stroke onset. To clarify the conflicting effects on stroke onset, we examined the expression of endogenous BDNF in relation to stroke onset. In addition, we explored the effect of exogenous central BDNF against stroke onset and all-cause mortality as the primary endpoint and BP as the secondary object in hypertensive rats with high-salt diet. In experiment 1, male spontaneously hypertensive stroke-prone rats (SHRSP) were fed a 0.3% (n = 8) or an 8% (n = 22) sodium diet (Na) through 28 days. The SHRSP with 8% Na showed significant increase of stroke onset, all-cause mortality, upregulation of reactive astrocytes, and disruption of blood-brain barrier. BDNF in the rats with 8% Na was significantly upregulated and mainly expressed in reactive astrocytes, whereas phosphorylated tropomyosin-related kinase B did not change by the rich BDNF. In experiment 2, male SHRSP were treated with continuous intracerebroventricular injection of 2.1 μg/day BDNF (n = 10) or the vehicle (Phosphate buffer saline; n = 10) and fed an 8% Na through 24 days. Exogenous central BDNF induced significant increase of BP and heart rate, and exhibited higher stroke onset and all-cause mortality compared with vehicle group. The present study demonstrated that endogenous BDNF were significantly produced in reactive astrocytes in relation to stroke onset regardless of neuroprotection. In addition, exogenous central BDNF increased BP which might be associated with sympathetic nerve activity and provided unfavorable effects on the prognosis of hypertensive rats. As BDNF is still potentially a good candidate for the treatment of neurovascular diseases, we suggest that hypertensive patients need care for the elevation of BP in the clinical trials of BDNF.
脑源性神经营养因子（BDNF）已知对多种神经血管疾病具有神经保护作用，尤其是在脑卒中后恢复方面。另一方面，BDNF 据报道可升高血压（BP），这是脑卒中发病的主要危险因素之一。为了阐明其对脑卒中发病的相互矛盾的影响，我们检查了内源性 BDNF 的表达与脑卒中发病的关系。此外，我们在高盐饮食的高血压大鼠中探索了外源性中枢 BDNF 对脑卒中发病和全因死亡率的作用（主要终点）以及 BP（次要终点）的影响。在实验 1 中，雄性自发性高血压脑卒中易感大鼠（SHRSP）在 28 天内接受 0.3%（n=8）或 8%（n=22）钠饮食（Na）。8%Na 的 SHRSP 脑卒中发病、全因死亡率显著增加，反应性星形胶质细胞上调，血脑屏障破坏。8%Na 的大鼠 BDNF 显著上调，主要表达于反应性星形胶质细胞，而富含 BDNF 并未改变磷酸化原肌球蛋白相关激酶 B。在实验 2 中，雄性 SHRSP 接受持续的脑室内注射 2.1μg/天 BDNF（n=10）或载体（磷酸盐缓冲盐水；n=10），并在 24 天内接受 8%Na 饮食。外源性中枢 BDNF 引起 BP 和心率显著升高，与载体组相比，脑卒中发病和全因死亡率更高。本研究表明，内源性 BDNF 与脑卒中发病相关，无论是否具有神经保护作用，均在反应性星形胶质细胞中大量产生。此外，外源性中枢 BDNF 升高 BP，这可能与交感神经活动有关，并对高血压大鼠的预后产生不利影响。由于 BDNF 仍然是神经血管疾病治疗的潜在候选药物，我们建议高血压患者在 BDNF 的临床试验中需要注意 BP 的升高。
