In normal rat, intraventricularly administered insulin-like growth factor-1 is rapidly cleared from CSF with limited distribution into brain

摘要

Background Putatively active drugs are often intraventricularly administered to gain direct access to brain and circumvent the blood-brain barrier. A few studies on the normal central nervous system (CNS) have shown, however, that the distribution of materials after intraventricular injections is much more limited than presumed and their exit from cerebrospinal fluid (CSF) is more rapid than generally believed. In this study, we report the intracranial distribution and the clearance from CSF and adjacent CNS tissue of radiolabeled insulin-like growth factor-1 after injection into one lateral ventricle of the normal rat brain. Methods Under barbiturate anesthesia, 125I-labeled insulin-like growth factor-1 (IGF-1) was injected into one lateral ventricle of normal Sprague-Dawley rats. The subsequent distribution of IGF-1 through the cerebrospinal fluid (CSF) system and into brain, cerebral blood vessels, and systemic blood was measured over time by gamma counting and quantitative autoradiography (QAR). Results Within 5 min of infusion, IGF-1 had spread from the infused lateral ventricle into and through the third and fourth ventricles. At this time, 25% of the infused IGF-1 had disappeared from the CSF-brain-meningeal system; the half time of this loss was 12 min. The plasma concentration of cleared IGF-1 was, however, very low from 2 to 9 min and only began to rise markedly after 20 min. This delay between loss and gain plus the lack of radiotracer in the cortical subarachnoid space suggested that much of the IGF-1 was cleared into blood via the cranial and/or spinal nerve roots and their associated lymphatic systems rather than periventricular tissue and arachnoid villi. Less than 10% of the injected radioactivity remained in the CSF-brain system after 180 min. The CSF and arteries and arterioles within the subarachnoid cisterns were labeled with IGF-1 within 10 min. Between 60 and 180 min, most of the radioactivity within the cranium was retained within and around these blood vessels and by periaqueductal gray matter. Tissue profiles at two sites next to ventricular CSF showed that IGF-1 penetrated less than 1.25 mm into brain tissue and appreciable 125I-activity remained at the tissue-ventricular CSF interface after 180 min. Conclusion Our findings suggest that entry of IGF-1 into normal brain parenchyma after lateral ventricle administration is limited by rapid clearance from CSF and brain and slow movement, apparently by diffusion, into the periventricular tissue. Various growth factors and other neuroactive agents have been reported to be neuroprotective within the injured brain after intraventricular administration. It is postulated that the delivery of such factors to neurons and glia in the injured brain may be facilitated by abnormal CSF flow. These several observations suggest that the flow of CSF and entrained solutes may differ considerably between normal and abnormal brain and even among various neuropathologies.