Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

Dynamic alterations of cerebral pial microcirculation during experimental subarachnoid hemorrhage.

The study aimed to investigate the involvement of cerebral microcirculation turbulence after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH and SAH groups. Autologous arterial hemolysate was injected into rat's cisterna magna to induce SAH. Changes of pial microcirculation within 2 h were observed. It was found that there were no obvious changes of the diameters, flow velocity, and fluid state of microvessels in non-SAH group. With the exception of rare linear-granular flow in A4 arteriole, linear flow was observed in most of the arterioles. There was no blood agglutination in any of the arterioles. After SAH, abnormal cerebral pial microcirculation was found. Spasm of microvessels, decreased blood flow, and agglutination of red blood cells occurred. Five minutes following the induction of SAH, the diameters of the arterioles and venules significantly decreased. The decreased diameters persisted for 2 h after cisternal injection. Decreased flow velocity of venules was found from 5 to 90 min after induction of SAH. Spasm of the basilar artery and increased brain malondialdehyde were also found after SAH. We concluded that cerebral microcirculation turbulence plays an important role in the development of secondary cerebral ischemia following SAH.

Zinc protoporphyrin aggravates cerebral ischemic injury following experimental subarachnoid hemorrhage.

This study was aimed to evaluate the influence of an antagonist of heme oxygenase, zinc protoporphyrin IX (ZnPPIX), on the production of endogenous carbon monoxide (CO) and the secondary cerebral injury after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, and ZnPPIX groups. Autologus arterial hemolysate was injected into rat cisterna magna to induce SAH. CO and cyclic guanosine monophosphate (cGMP) levels in the brain, and lactate dehydrogenase (LDH) activity in serum were determined 24 hours and 72 hours after cisternal injection. It was found that 24 hours and 72 hours after SAH, the CO contents in SAH group were increased by 20.76% and 37.36%, respectively. CO content in ZnPPIX group was statistically lower than that in SAH group. No obvious change of cGMP content in SAH group was found. However, cGMP content in ZnPPIX group was lower than that in SAH group. Serum LDH activity increased significantly after induction of SAH. LDH activity in ZnPPIX group increased to a greater extent. It was concluded that ZnPPIX aggravates the cerebral injury secondary to experimental SAH by inhibiting the production of endogenous CO. The activation of HO/CO pathway is an intrinsic protective mechanism against cerebral ischemic injury after SAH.