Vincent S. Hau

Noscapine Crosses the Blood-Brain Barrier and Inhibits Glioblastoma Growth

The opium alkaloid noscapine is a commonly used antitussive agent available in Europe, Asia, and South America. Although the mechanism by which it suppresses coughing is currently unknown, it is presumed to involve the central nervous system. In addition to its antitussive action, noscapine also binds to tubulin and alters microtubule dynamics in vitro and in vivo. In this study, we show that noscapine inhibits the proliferation of rat C6 glioma cells in vitro (IC50 = 100 μm) and effectively crosses the blood-brain barrier at rates similar to the ones found for agents such as morphine and [Met]enkephalin that have potent central nervous system activity (P ≤ 0.05). Daily oral noscapine treatment (300 mg/kg) administered to immunodeficient mice having stereotactically implanted rat C6 glioblasoma into the striatum revealed a significant reduction of tumor volume (P ≤ 0.05). This was achieved with no identifiable toxicity to the duodenum, spleen, liver, or hematopoietic cells as determined by pathological microscopic examination of these tissues and flow cytometry. Furthermore, noscapine treatment resulted in little evidence of toxicity to dorsal root ganglia cultures as measured by inhibition of neurite outgrowth and yielded no evidence of peripheral neuropathy in animals. However, evidence of vasodilation was observed in noscapine-treated brain tissue. These unique properties of noscapine, including its ability to cross the blood-brain barrier, interfere with microtubule dynamics, arrest tumor cell division, reduce tumor growth, and minimally affect other dividing tissues and peripheral nerves, warrant additional investigation of its therapeutic potential.

Time-dependent sensitization of plasma beta-endorphin in community elderly with self-reported environmental chemical odor intolerance

This study examined plasma beta-endorphin as a marker of the physiological stress response in community elderly who were either high (n = 15) or low (n = 15) in self-rated frequency of illness from environmental chemical odors. Individuals who report nonatopic multiple sensitivities to or intolerances for low levels of environmental chemicals also claim high rates of comorbid food sensitivities or intolerances. Subjects gave 9 AM blood samples for plasma beta-endorphin 90 min after ingesting either 1% fat cows milk or a soy-based nondairy drink, on six different mornings in the laboratory after all-night sleep recordings. The six sessions-were divided into three sets of two successive days each, with each set [involving baseline (ad lib milk), nondairy (soy-based), and dairy diets] separated from the next by 3 weeks. In the chemically tolerant subjects, stably lower beta-endorphin levels suggested that milk may have been a physiologically less stressful beverage than was the soy drink. In contrast, the chemical odor intolerant group exhibited a) increased levels of plasma beta-endorphin averaged over the 6 days (p = .02); and b) marked fluctuations in endorphin from one laboratory day to the next (Group x Diet x Day interaction, p = .005). The findings were consistent with time-dependent, context-dependent sensitization of beta-endorphin in the chemical odor intolerant individuals.

Effect of λ-carrageenan-induced inflammatory pain on brain uptake of codeine and antinociception

Abstract This study investigated the potential clinical implications of λ-carrageenan-induced inflammatory pain on brain uptake of a commonly used analgesic, codeine, in relation to the fundamental properties of the blood–brain barrier (BBB) correlated to its antinociceptive profile over a 168-h time course. BBB uptake of [14C]sucrose (a membrane impermeant marker) and [3H]codeine were investigated using an in situ brain perfusion model in the rat. Results demonstrated a significantly increased brain uptake of [14C]sucrose at 1, 3, 6 and 48 h (139±9%, 166±19%, 138±13% and 146±7% compared with control, respectively) and [3H]codeine at 3 and 48 h (179±6% and 179±12% compared with control, respectively). Capillary depletion analyses ensured that increased radioisotope associated with the brain was due to increased uptake rather than trapping in the cerebral vasculature. Antinociception studies using a radiant-heat tail flick analgesia method demonstrated that λ-carrageenan-induced inflammatory pain enhanced the in vivo antinociceptive profile of i.p.-administered codeine (7 mg/kg) at 3 and 48 h (144±11% and 155±9% compared with control, respectively). This study demonstrated that brain uptake and antinociception of codeine are increased during λ-carrageenan-induced inflammatory pain, suggesting that the presence of inflammatory pain may be an important consideration in therapeutic drug dosing, potential adverse effects and/or neurotoxicity.

Viability of microvascular endothelial cells to direct exposure of formalin, λ-carrageenan, and complete Freund's adjuvant

We investigated three inflammatory agents to establish if these substances elicit a direct effect on the functional and structural integrity of the blood-brain barrier. Cellular cytotoxicity and paracellular permeability were assessed in vitro using primary bovine brain microvascular endothelial cells exposed to formalin, lambda-carrageenan, or complete Freunds adjuvant for 1, 3, or 72 h, respectively. Results showed that only the highest concentration (0.025%) of formalin produced a decrease in cell viability (approximately 34%) and a significant increase in cell permeability to [(14)C]sucrose at 120 min (approximately 137%). Brain perfusion using female Sprague-Dawley rats showed no difference in paracellular permeability to [(14)C]sucrose for any inflammatory agent. Western blot analyses were performed on isolated rat brain microvessels to assess the structural integrity of blood-brain barrier tight junctions. Results indicate that expression of zonula occludens-1, occludin, claudin-1, and actin remain unchanged following intravenous exposure to inflammatory agents. This study confirms that changes seen at the blood-brain barrier following a peripheral inflammation are due to physiological responses to the given inflammatory agent and not to any direct interaction between the inflammatory agent and the brain microvasculature.