438 0090-2977/19/5106-00438 © 2019 Springer Science+Business Media LLC Neurophysiology, Vol. 51, No. 6, November, 2019 Physical Training Moderates Blood-Brain-Barrier Disruption and Improves Cognitive Dysfunction Related to Transient Brain Ischemia in Rats N. Shamsaei, 1 H. Abdi, 2 and F. Moradi 3 Received May 29, 2019 Cerebral ischemia induces structural and functional damage in the brain, which leads to cell death and cognitive dysfunction. According to the evidences, physical exercise training exerts a neuroprotective effect and may decrease ischemia-induced injuries in this case. We evaluated the protective effects of physical training on blood-brain-barrier (BBB) disruption, neuronal death, and cognitive dysfunction induced by cerebral ischemia in male rats. Thirty-six adult male rats were selected randomly and allocated into three groups, ischemia (I), ischemia+exercise (I+E), and sham (Sh). Brain ischemia was induced via occlusion of the common carotid arteries for 20 min. Before occlusion, animals of the I+E group ran on a treadmill 5 days a week for 4 weeks. Spatial memory performances of rats were evaluated by the Morris water maze test. Apoptotic cell death in the dentate gyrus (DG) of the hippocampus was detected by a TUNEL assay, while the level of disruption of the BBB was measured by an Evans blue assay. Cerebral ischemia caused spatial memory impairment; exercise training improved the index of memory impairment following ischemia significantly (P < 0.05). Also, exercise training significantly reduced the BBB permeability in I+E rats compared with the I group (P < 0.05). In addition, the number of TUNEL- positive cells was significantly greater in I rats, while exercise training significantly reduced apoptotic cell death (P < 0.05). Our results indicate that physical training exerts noticeable neuroprotective effects against brain ischemic injury, in particular by preserving the BBB integrity. Keywords: cerebral ischemia, physical exercise, blood-brain-barrier (BBB), cell death, cognitive dysfunction. 1 Department of Physical Education and Sport Sciences, Ilam University, Ilam, Iran. 2 Department of Physical Education and Sport Sciences, Payam-e Noor University, Tehran, Iran. 3 Department of Physiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. Correspondence should be addressed to N. Shamsaei (e-mail: shamsaeinabi@gmail.com), or to H. Abdi (e-mail: abdi197866@gmail.com), or to F. Moradi (e-mail: moradifatemeh98@yahoo.com). INTRODUCTION Reduction or cessation of blood flow to a part of the brain due to blockage of a cerebral artery leads to brain ischemia [1]. Cerebral ischemia is a standout cause of disability and death in the world, with over 80% of all cases activated by ischemic occasions [2]. Cerebral ischemia-reperfusion (IR) injury causes permanent degeneration in the CNS, which is a primary cause of death in neurological diseases [3]. During brain ischemia, cerebral blood flow, important metabolite levels, and that of oxygen are reduced; returned blood flow during reperfusion leads to intense cellular oxygenation and augmented generation of reactive oxygen species (ROSs). Then, the respective effects on cell signaling can lead to dramatic tissue damage [4]. Recent studies demonstrated that certain pathological features are related to the IR effects, including the creation of ROSs, energy failure, neuronal apoptosis, an inflammatory response, and, finally, to neurological dysfunction [5]. The hippocampus is vitally important for memory functions [6, 7]. This cerebral structure is more sensitive to ischemic insults than other areas of the brain. Ischemia readily leads to strong physical and functional damages in the hippocampus [8]. The blood-brain barrier (BBB) is a specialized endothelial structure in the CNS. The BBB is composed of specialized cerebral endothelial cells, which form a tight seal due to the presence of tight junctions, which restricts the entry of plasma components and blood cells into the brain [9]. Several neuropathological conditions, DOI 10.1007/s11062-020-09840-x