Reconstituted High-Density Lipoprotein Exhibits Neuroprotection in Two Rat Models of Stroke

Abstract

Background: Reconstituted high-density lipoprotein (rHDL) is prepared from apolipoprotein A-I, isolated from human plasma, and soybean-derived phosphatidylcholine and exhibits biochemical and functional characteristics similar to endogenous nascent high-density lipoprotein (HDL). This study tested the hypothesis that pretreatment with rHDL may reduce neuronal damage in 2 experimental rat models of stroke. Methods: In the first model, an excitotoxic lesion was induced by unilateral injection of N-methyl-D-aspartate (NMDA) in the right striatum (excitotoxic lesion model). In the second model, temporary occlusion of the middle cerebral artery (MCA) was attained by inserting a nylon thread through the carotid artery and blood flow was restored 30 min later (MCAo model). In both models, either rHDL (120 mg/kg) or saline (control) were infused over 4 h, starting 2 h before the injection of NMDA or the induction of ischemia, respectively. 24 h after the interventions, the rats were sacrificed and the brains removed for histochemical preparation. The necrotic area was delimited using an image analysis system. In addition, the levels of reactive oxygen species (ROS) in human endothelial (ECV 304) and neuroblastoma (SK-N-BE) cell lines were measured fluorometrically as 2′,7′-dichlorofluorescein fluorescence in the presence and absence of rHDL and under basal and stress-induced conditions. Results: In the excitotoxic lesion and MCAo models, pretreatment with rHDL significantly reduced the brain necrotic area by 61 and 76%, respectively (p < 0.01). Overnight incubation of ECV 304 and SK-N-BE cells with 0.5 mg/ml rHDL decreased basal and stress-induced ROS levels by 73 and 72% (ECV 304) and by 76 and 43% (SK-N-BE), respectively (p < 0.01). Conclusion: These results suggest that rHDL reduces neuronal damage after onset of ischemic stroke, possibly by involving an anti-oxidative mechanism. Thus, rHDL may be a powerful neuroprotective tool for the treatment of cerebrovascular diseases.

Cardioprotective functions of HDLs

“…In studies of experimental stroke in rats, pretreatment with rHDLs has also been shown to substantially reduce the brain necrotic area ( 83 ).…”

Protective Effect of High-Density Lipoprotein-Based Therapy in a Model of Embolic Stroke

“…After decapitation, brain sections were embedded in optimal cutting temperature medium and immediately frozen. Coronal sections (8 m; at ϩ0.70 mm posterior to bregma) 15 were prepared with the use of a cryostat. Cell nuclei were stained with 4Ј, 6Ј-diamidino-2-phenylindole (0.5 g/mL for 10 minutes) and the sections were observed under an epifluorescence microscope.…”

Reconstituted High-Density Lipoproteins Inhibit the Acute Pro-Oxidant and Proinflammatory Vascular Changes Induced by a Periarterial Collar in Normocholesterolemic Rabbits

“…6 Also, in studies of experimental stroke in rats, pretreatment with rHDL significantly and substantially reduced the brain necrotic area in a process possibly related to an rHDL-induced reduction in levels of reactive oxygen species (ROS). 7 Furthermore, in a study of hemorrhagic shock in rats, the resulting multiple organ dysfunction syndrome was largely abolished by a single injection of human HDL given 90 minutes after the hemorrhage and 1 minute before resuscitation. In that model, injection of HDL prevented both the severe disruption of tissue architecture and the extensive cellular infiltration into the affected tissues.…”