A Mathematical Model for Prediction of Drug Molecule Diffusion Across the Blood-Brain Barrier

Background:Predicting the ability of drugs to enter the brain is a longstanding problem in neuropharmacology. The first step in creating a much-needed computational algorithm for predicting whether a drug will enter brain is to devise a rigorous mathematical model.Methods:Employing two experimental measures of blood-brain barrier (BBB) penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors, a mathematical model was developed to quantitatively correlate molecular structure with ability to traverse the BBB.Results:This mathematical model employs Stein's hydrogen bonding number and Randic's topological descriptors to correlate structure with ability to cross the BBB. The final model accurately predicts the ability of test molecules to cross the BBB.Conclusion:A mathematical method to predict blood-brain barrier penetrability of drug molecules has been successfully devised. As a result of bioinformatics, chemoinformatics and other informatics-based technologies, the number of small molecules being developed as potential therapeutics is increasing exponentially. A biophysically rigorous method to predict BBB penetrability will be a much-needed tool for the evaluation of these molecules.

Species variation in pesticide-induced blood-brain barrier dysfunction

Neurological disorders following acute or chronic exposure to pesticides have been reported in a number of human cases. However, the mechanism(s) by which pesticides produce central nervous system dysfunction is not clear. The objective of the present study was to examine the functional status of blood-brain barrier (BBB) in rats and mice exposed to selected pesticides of different chemical groups. Adult male albino rats and mice were exposed (1/10 of LD50) daily to dichlorvos (organophosphate), lindane (organochlorine) and carbofuran (carbamate) through oral intubation for 3 days. The status of BBB was evaluated by determining brain sodium fluorescein dye uptake and brain uptake index (BUI) in relation to serum dye level. The brain dye uptake and BUI in pesticide-exposed rats did not differ significantly in comparison to that of controls. However, brain dye uptake and BUI were increased significantly in mice exposed to dichlorvos (85%, 40%), lindane (79%, 26%) and carbofuran (129%, 61%). The results of this study show that mouse BBB system is more sensitive to pesticide-induced breach as compared to that of rat. These variations may have a role in determining the outcome of pesticide neurotoxicity in different species.

Functional impairment of blood-brain barrier following pesticide exposure during early development in rats

1 The effect of certain pesticides on the functional integrity of the developing blood-brain barrier (BBB) was studied following single and repeated exposure, and after subsequent withdrawal in rats. 2 Ten-day-old rat pups exposed orally to quinalphos (QP, organophosphate), cypermethrin (CM, pyre-throid) and lindane (LD, organochlorine) at a dose of 1/50th of LD50, showed a significant increase in the brain uptake index (BUI) for a micromolecular tracer, sodium fluorescein (SF), by 97, 37 and 72%, respectively, after 2 h. Residual increases in the BUI were found even after 3 days of the single treatment of QP (28%) and LD (23%). 3 Repeated exposure for 8 days (postnatal days (PND) 10-17) with QP, CM and LD increased the BBB permeability by 130, 80 and 50%, respectively. Recovery from these changes was complete in QP and LD-treated animals after 13 days (PND 18-30) of withdrawal. However, CM showed persistent effects that were normalized only after 43 days (PND 18-60) of withdrawal. 4 A single dose reduced to 1/100th of LD50 also increased BUI in 10-day-old rat pups following QP (20%) and CM (28%) exposure at 2 h. 5 An age-dependent effect of these pesticides was evident from the study showing higher magnitude of BUI changes in 10-day-old rats as compared to that in 15- day-old rats. Furthermore, adult rats did not show any effect on BBB permeability even at a higher dose (1/25th of LD50) of these pesticides given alone or in combination with piperonyl butoxide (600 mg/kg, i.p.) for 3 consecutive days. 6 This study showed that developing BBB is highly vulnerable to single or repeated exposure of certain pesticides. The observed persistent effects during brain development even after withdrawal of the treatment may produce some neurological dysfunction at later life as well.

Transient blood-brain barrier passage of polar compounds at low pH

The brain uptake index (BUI) of polar 14C-labeled test compounds with molecular weights (MWs) of 79-70,000 was examined using the single-pass carotid injection technique in pentobarbital-anesthetized rats. Compounds were injected in 40 mM malonate, pH 2.5, and 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4. BUI is defined as (14C-labeled test compound/[3H]H2O in brain)/(14C-labeled test compound/[3H]H2O in injectate) x 100 at a 5-s decapitation time. Increased BUIs of compounds in pH 2.5 buffer were MW dependent with a threshold < 5,000. BUI, extraction, and permeability-surface area product (PS) were significantly greater at pH 2.5 compared with pH 7.4 (P < 0.05). Washouts of [14C]butanol and [3H]H2O at pH 2.5 and pH 7.4 were calculated. Cerebral blood flow and PS increased at low pH. Other buffers, oxalate, glycine, and lactate were used at low pH and also increased BUIs. The duration of the blood-brain barrier (BBB) opening at pH 2.5 was 60 s as estimated by penetrance of the normally excluded dye fluorescein. A plot of BUI or PS at pH 2.5 vs. (MW)1/2 suggests that transient BBB tight junction opening contributed to the passage of polar compounds at low pH.

Vitamin E Uptake into the Brain and 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity

The brain uptake index for vitamin E has not been reported previously. This study examined the possible involvement of altered brain vitamin E uptake as an explanation of alterations in vitamin E levels in the brain following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. The brain uptake index of vitamin E was evaluated in control mice and at 1 and 24 h after toxin treatment. Control mice had a brain uptake index of 6.1 ± 1.2. The toxin induced more than a twofold increase in the vitamin E brain uptake index to 15.2 ± 6.8 at 1 h after treatment, which returned to control values at 24 h. The dramatic increase in the brain uptake index of vitamin E may explain the increases in vitamin E levels found in some brain regions following MPTP administration.

Metabolic fuel and amino acid transport into the brain in experimental hypothyroidism

The effect of hypothyroidism in the adult rat on blood-brain barrier and muscle transport of hexoses, neutral amino acids, basic amino acids, monocarboxylic acids, and ketone bodies was examined using single arterial injection-tissue sampling technique. The cerebral blood flow and brain extraction of 3H2O (internal reference substance) was not altered in 3-month-old hypothyroid rats maintained on methimazole, 0.025% in the drinking water, for 7 weeks. The brain uptake index of D-β-hydroxybutyrate was significantly reduced in hypothyroid rats (2.4 ± 0.3 vs 4.6 ± 0.6% p<0.001). Hypothyroid rats given thyroid hormone replacement therapy had normal brain uptake of D-β-hydroxybutyrate (4.4 ± 0.8%). The brain uptake index of butyrate was also significantly reduced in hypothyroid rats (39.3 ± 2.1 vs 47.2 ± 0.74%, p<0.001). The brain uptake index of other test substances and muscle uptake of nutrients examined were not altered in hypothyroid rats. These studies indicate that of the four transport systems examined in two tissues, the blood-brain barrier monocarboxylic acid transport system is most susceptible to the hypothyroidism-induced changes.