Enhanced cerebrovascular permeability by Metrazol: significance for brain metastases

Abstract

Metrazol enhanced the penetration of two proteins (125I human serum albumin and horseradish peroxidase), and the anticancer agent, razoxane, into the central nervous system of anaesthetized rats. Penetration was increased throughout the whole brain. With the exception of the bladder, no peripheral tissue was affected. The increase in brain permeability was temporary and reversed within 4 hours; brain levels of drug and protein were increased by up to three times.

Short communication: Metrazol enhances brain penetration and therapeutic efficacy of some anticancer agents: implications for brain metastases

“…Studies with radiolabelled albumin and horseradish peroxidase have demonstrated that all brain areas are affected, from the olfactory lobes rostrally to the medulla oblongata caudally [6,12]. Studies with radiolabelled albumin and horseradish peroxidase have demonstrated that all brain areas are affected, from the olfactory lobes rostrally to the medulla oblongata caudally [6,12].…”

“…tumours there has been considerable research into the development of innocuous techniques to increase the cerebrovascular permeability of normally excluded substances of potential use in brain tumour chemotherapy [6,[14][15][16]. tumours there has been considerable research into the development of innocuous techniques to increase the cerebrovascular permeability of normally excluded substances of potential use in brain tumour chemotherapy [6,[14][15][16].…”

“…Metrazol, pentylenetetrazol, a CNS stimulant which at high concentrations acts as an analeptic, has been shown to increase the brain penetration of the sparingly water-soluble anticancer agent razoxane in anaesthetized rats by a factor of 2"6 [6]. Quantitative studies with intravascular protein markers have demonstrated that these alterations in cerebrovascular permeability are temporary and reversed within 4 hours [6,12].…”

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

“…Short-and long-term effects on both the structure and function of the central nervous system would be likely to follow traumatic events (i.e., convulsive seizures) to the microvasculature. Blood flow and permeability changes have been reported to follow drug-induced seizures (Greig and Hellmann, 1983;Ingvar et al, 1984;Ruth, 1984;Ziylan and Ates, 1989;Johansson and Linder, 1978). However, it is unclear to what extent anesthesia used in some of these studies may have affected the results, since such procedures are known to dramatically alter blood flow, permeability measures (Goldman and Sapirstein, 1973), and the neuroexcitatory effects of convulsants.…”

Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain

“…The most thoroughly studied method for enhancement of brain tissue uptake is the intracarotid infusion of a hyperosmotic solution, which opens tight junctions between brain capillary endothelial cells and increases passive diffusion of polar compounds into the brain [10,11]. Other pharmacologic agents that appear to increase brain tissue exposure to systemic substrates, perhaps by increasing the permeability of the blood -brain barrier through differing mechanisms, include ethanol [12], oleic acid [13], pentylenetetrazol [14], dimethyl sulphoxide [15], insulin [16], and valproic acid [17]. Efflux blockade also has been explored as a method of increasing CNS drug exposure.…”