1. Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves
Functional Recovery Following Subarachnoid Hemorrhage
Byung H. Han, Fadi Abousaleh, Eric Milner, Samuel N. Edeh, John Kaminski, and
Gregory J. Zipfel
Department of Neurological Surgery, Washington University School of Medicine 660 S.
Euclid Avenue, St. Louis, MO 63110
Aneurysmal subarachnoid hemorrhage (SAH) is characterized by rupture of an
intracranial aneurysm leading to abrupt extravasation of blood into the subarachnoid
space. The devastating outcome after SAH is believed to be associated with early brain
injury due to an acute ischemic insult as well as secondary events such as cerebral
vasospasm. Many studies suggest that SAH-induced vasospasm is attributed to
impairment of nitric oxide (NO)-mediated vasodilation pathways, including endothelial
NO synthase, guanylate cylases, phosphodiesterases (PDE), and cyclic guanosine
monophosphate (cGMP) levels in cerebral vessels. Recent data suggest that in particular
the phosphodiesterase isoform, PDE5, may play a significant pathophysiologic role in
SAH-induced vasospasm, as the PDE5 specific inhibitor sildenafil has been shown in two
preliminary studies to attenuate cerebral vasospasm following experimental SAH.
Whether PDE5 inhibition leads to improved functional recovery after SAH, however, has
yet to be examined.
In this study, male C57BL6 mice underwent experimental SAH via endovascular
perforation of the left anterior cerebral artery and received sildenafil (2 mg/kg, P.O. BID)
or vehicle for 3 days beginning 2 hours after SAH. Behavioral performance was assessed
via sensorimotor neurological score and rotarod latency test. Three days after SAH,
cerebral vasospasm was assessed via gelatin/India ink casting of the cerebrovasculature
and measurement of ipsilateral proximal middle cerebral artery (MCA) diameter. We
found that sildenafil markedly inhibited cerebral vasospasm in the MCA (70.1 ± 5.3 µm
vs. 92.9 ± 6.6 µm, P < 0.05). Most importantly, we also documented a marked reduction
in SAH-induced neurologic deficits in sildenafil-treated vs. vehicle-treated animals.
Specifically, mice administered sildenafil as compared to vehicle showed marked
reduction in rotarod latency (90.2 ± 14.7 sec vs. 136.8 ± 12.6 sec, P < 0.05) and
significant improvement in neurological score (15.8 ± 1.4 vs. 19.1 ± 1.2, P < 0.05) 3 days
after experimental SAH. Moreover, sildenafil treatment did not affect behavioral
performance or systemic blood pressure in control mice. These data suggest that PDE5
inhibition via sildenafil administration is a promising new therapeutic approach towards
the amelioration of cerebral vasospasm following SAH.