Elsevier

Brain Research

Volume 905, Issues 1–2, 29 June 2001, Pages 81-90
Brain Research

Research report
The effect of bone morphogenetic protein-7 (BMP-7) on functional recovery, local cerebral glucose utilization and blood flow after transient focal cerebral ischemia in rats

https://doi.org/10.1016/S0006-8993(01)02502-1Get rights and content

Abstract

Bone morphogenetic protein-7 (BMP-7) has been shown to enhance dendritic growth and improve functional recovery after experimental stroke. In this study, we examined the effect of BMP-7 on functional recovery, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) following transient middle cerebral artery occlusion. Sprague–Dawley rats (n=29) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by poly-l-lysine-coated intraluminal suture. Rectal and cranial temperatures were regulated at 37.0–37.5°C. BMP-7 or vehicle (volume, 25 μ1) was administered intracisternally in a blinded fashion at 24 h after MCAo. Neurological status was evaluated during occlusion (60 min) and daily for 2 days after MCAo. In matched animal groups, LCMRglu was measured autoradiographically with [14C]2-deoxyglucose (2-DG) and LCBF with [14C]iodoantipyrine 48 h after MCAo. Four animals groups were studied: LCMRglu series (BMP-7, n=7; vehicle, n=8); LCBF series (BMP-7, n=6; vehicle, n=8). Average three-dimensional image data sets were constructed for each group and were compared by pixel-based statistical methods. Rectal and cranial temperatures, mean blood pressure, plasma glucose and blood gases were similar among groups. BMP-7 significantly improved the total neurological score compared to vehicle at 48 h after MCAo (7.3±0.4 vs. 9.0±0.2, respectively; P<0.0003). Compared to vehicle-rats, BMP-7 enhanced glucose utilization in the basal ganglia ipsilateral to stroke and improved LCBF in ipsilateral subthalamus, but decreased LCBF and LCMRglu in contralateral cortical regions.

Introduction

Bone morphogenetic protein-7 (BMP-7), also known as osteogenic protein-1 (OP-1), is a member of the transforming growth factor-β (TGF-β) superfamily and has been documented to be a trophic factor for bone and cartilage [38]. Recent studies, however, indicate that the effects of BMP-7 are not limited to the skeletal system. BMP-7 is expressed in fetal kidney, heart, teeth, eye, bone, intestine and in perinatal neuronal tissues (e.g., hippocampus, cortex and cerebellum) [6], [9], [24]. BMP-7 selectively promotes dendritic growth in cultured sympathetic and CNS neurons — a property that distinguishes it from most other identified growth factors, which largely support axonal outgrowth [37].

Recent reports indicate that BMP-7 exerts neuroprotective effects in the CNS. When administered 24 h after permanent focal cerebral ischemia, BMP-7 led to a significant improvement in the recovery of motor skills without affecting infarction volume [14]. It was suggested that this effect might have been due to its dendritic outgrowth-promoting activity [21], [27]. It is possible that BMP-7 may have additional mechanisms that promote behavioral recovery after stroke.

We hypothesized that metabolic or hemodynamic factors might contribute to the salutary effect of BMP-7 in focal cerebral ischemia. These factors have not been previously investigated. Thus, the intent of the present study was to examine the effect of BMP-7 on functional recovery, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) in a highly reproducible model of middle cerebral artery occlusion in rats [2].

Section snippets

Surgical preparation

Twenty-nine adult male Sprague–Dawley rats (280–335 g, Crl:CD (SD)BR strain, Charles River Laboratories, Wilmington, MA) were used in these studies. The University of Miami’s Animal Care and Use Committee approved all study protocols. Animals were fasted overnight but were allowed free access to water. Following atropine sulfate (0.5 mg/kg, i.p.), anesthesia was induced with 3.5% halothane in a mixture of 70% nitrous oxide and a balance of oxygen. Rats were orally intubated, immobilized with

Physiological variables

Rectal and cranial (temporalis muscle) temperatures, arterial blood pressure, blood gases, and plasma glucose in the 29 animals studied showed no significant differences among groups when measured before MCAo, during MCAo, and at 15 min, and 24 and 48 h after MCAo. Representative data are shown in Table 1. Although all animals lost weight transiently after surgery, there were no significant differences in body weight between vehicle- and BMP-7-treated rats on days 1 or 2 following ischemia (

Discussion

We found that intracisternal injection of BMP-7, administered 24 h after stroke, moderately enhanced the recovery of sensorimotor function following middle cerebral artery occlusion in rats. In addition, BMP-7 significantly increased LCMRglu in ipsilateral basal ganglia, improved LCBF in ipsilateral subthalamic area, and decreased LCBF and LCMRglu in contralateral cortical regions.

Observation of neurological deficits is important not only in clinical stroke patients but also in animal models of

Acknowledgements

Supported by Creative BioMolecules, Inc., Hopkinton, MA, and by NIH Grant NS 05820. The authors thank Judith Y. Loor for expert technical assistance.

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