Pentoxifylline Alleviates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage.
Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease frequently caused by ruptured aneurysms. Early brain injury (EBI) is the primary cause of morbidity and mortality in patients diagnosed with SAH and is associated with increased intracranial pressure, decreased cerebral blood flow and cerebral ischemia. Pentoxifylline (PTX) is a methylxanthine derivative clinically proven to improve perfusion in the peripheral microcirculation and has been shown to have neuroprotective effects in brain trauma and global cerebral ischemia in experimental animal models. This study aimed to determine the effect of PTX in experimental SAH, which has not been investigated yet.



An experimental SAH model was induced in male Wistar rats by autologous blood injection into the prechiasmatic cistern, and PTX was injected intraperitoneally immediately after SAH. The effects of PTX were evaluated 24 h after SAH via assessing the cerebral ultrastructure via transmission electron microscopy (TEM). Brain edema, blood-brain barrier (BBB) permeability, red blood cell deformability, tumor necrosis factor-alpha (TNF-alpha), nitrite-nitrate levels and apoptotic neuron death were also determined 24 h after SAH. The BBB permeability was measured by Evans blue (EB) extravasation, erythrocyte deformability was determined by filtration technique, and TNF-alpha and reactive nitrogen metobolites were analyzed in brain tissue by ELISA and spectral analysis, respectively. Apoptotic neurons were determined in brain sections by cleaved caspase-3 immunohistochemical analysis, and expression intensity was quantified using image J software.



Cerebral ultrastructure in SAH group animals revealed intense perivascular edema and distortion in the astrocyte foot processes. PTX treatment attenuated structural deterioration due to SAH. Brain water content, BBB permeability, TNF-alpha, nitrite-nitrate levels and apoptotic neuronal death were significantly increased 24 h after SAH and were significantly alleviated by PTX treatment. There was no significant change in red cell deformability after SAH.



Our results show that PTX reduces brain edema, BBB permeability, TNF-alpha expression, reactive nitrogen metobolites and apopotosis in experimental SAH. Based on our findings we suggest that PTX exerts neuroprotection against SAH-induced EBI, which might be associated with the inhibition of inflammation and apoptotic neuronal cell death.
Department of Neurosurgery, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Ethem
E
Goksu
Division of Neurosurgery, Denizli State Hospital, Denizli, 20125, Turkey.
Ozgur
O
Dogan
Department of Physiology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Pınar
P
Ulker
Department of Histology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Gamze
G
Tanrıover
Department of Histology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Esma
E
Konuk
Department of Histology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Sayra
S
Dilmac
Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Ebru
E
Kirac
Department of Histology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey.
Necdet
N
Demır
Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey. mutayaslan@akdeniz.edu.tr.
Mutay
0000-0002-0660-971X
M
Aslan
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control*; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy*
D018696:Neuroprotective Agents; D010431:Pentoxifylline
Apoptosis; Early brain injury; Inflammation; Pentoxifylline; Subarachnoid hemorrhage