by Ba Hoang, MD, PhD

A New Model for Asthma Set Out in Three Papers by Ba Hoang, MD, PhD

2006

Bronchial Epilepsy or Bronchopulmonary Hyper-excitability as a Model of Asthma

Pathogenesis1

The first of three papers reframing asthma as a form of ”bronchial epilepsy” was published in 2006 by Ba Hoang, MD, PhD, and colleagues. It proposes that asthma may be, at root, a syndrome of inducible, genetically predisposed membrane hyperexcitability. Though inflammation and allergy are highly correlated with asthma, they are not always present. In active asthma, however, bronchoconstriction is always present. The action of nerves, muscles, hormones, and neurotransmitters relies on cell excitability. Cells are excited by the reversal of resting membrane potential, and this reversal is mediated through what are known as gated ion channels. Most of the cell membrane is made of lipids, fatty molecules that act as a barrier to ions (electrically charged atoms) such as sodium, calcium, chloride, and potassium. Embedded in the cell membrane are special protein ”gatekeepers” known as ion channels that control the movement of ions. They open and close in response to a change in the electrical charge difference that is naturally generated across the cell membrane, or in response to molecular signals from inside or outside the cell. These ion channels are either excitatory or inhibitory. The major excitatory ion channels are glutamate- and acetylcholine-responsive. When these channels are activated, their electrical activity increases.2 Glutamate has an excitotoxic action, and its action in the lungs of rats mimics the asthmatic response. In contrast, gamma aminobutyric acid (GABA) has an inhibitory, calming action, and GABA agonists inhibit bronchoconstriction, cough, and airway inflammation in animal studies.3 In addition, the authors suggest that sodium channels may be involved in membrane excitability (and asthma pathogenesis).4,5 Sodium influx can follow acetylcholine release, resulting in smooth muscle contraction. It is interesting to note that sodium channel blockers such as lidocaine (inhaled or intravenous) and phenytoin (an antiseizure medication) are effective in both epilepsy and asthma.6,7 Phenytoin blocks voltage-sensitive sodium channels. Studies have shown that lidocaine has potential as an asthma therapy even for patients with severe steroid-dependent asthma,8 and, like phenytoin, acts on voltage-sensitive sodium channels to block repetitive firing of neurons. Phenytoin is helpful for acute and paroxysmal asthma, and a majority of treated patients were found to have sustained benefit from the therapy after phenytoin was discontinued.9,10 The paper by Ba and his colleagues concludes that better asthma control and prevention might be attained if we explore the role of proven excitotoxins in food and the environment. In addition, since the ketogenic diet,11 glycine and taurine supplementation,12 and inhibition of glutamate have proven to be helpful therapies in epilepsy, the same might hold true of asthma.

TAKEAWAY

Asthma may be, at root, a syndrome of inducible, genetically predisposed membrane hyperexcitability.

2007

New Approach in Asthma Treatment Using Excitatory

Modulator13

In this 2007 study, Ba and colleagues test their hypothesis (that asthma is induced by excitotoxins) by utilizing an herb called Sophora flavescens on 14 individuals suffering from moderate to severe asthma. S. flavescens has long been used as an anti-asthmatic agent in traditional Chinese medicine. In addition to anti-inflammatory and antioxidant effects,14,15 the herb contains two matrine-type alkaloids— matrine and oxymatrine—which can act as modulators of membrane excitability.16 Six men and eight women, aged 22–70, were treated during the time period from February 1997 to December 2005. These patients had been diagnosed with asthma by their allergists and had been on medication for asthma for three to six years. Despite years of moderate to high doses of inhaled corticosteroids and beta2-agonists, they still suffered from episodes of dyspnea, expectoration, coughing, wheezing, or chest tightness more than two times a week and were waking up at night with asthma symptoms more than two times a week.

Patients were given capsules with a dose equal to 4 g of dried S. flavescens root with a progressively diminishing dose: thrice daily for three months, twice daily for six months, and once daily for 27 months thereafter. All patients had been followed for three years. The patients were evaluated every two weeks for the first month, once monthly for the next six months and every three months thereafter. A dried powder of a standard hot water

extract was used because it has been shown to contain a high content of matrine and oxymatrine (1.8%–3.2%). This corresponds to about 72–128 μg of matrine and oxymatrine, when taken three times daily. Results were based on the diaries of symptoms, PEF (peak expiratory flow, which is the maximum airflow during a forced expiration beginning with the lungs fully inflated), medication use, and quality of life. Within the first two weeks, daytime asthma symptoms dropped by 65% and nighttime symptoms by 72%. Beta2-agonist medications were reduced by 67%. The dose of inhaled corticosteroids remained unchanged. The mean PEF rate improved by 9%. By one month, daytime asthma symptoms were reduced by 78%, and nighttime symptoms by 75%. The beta2-agonist dose was reduced by 72% and the dose of corticosteroid inhaler reduced by 45%. The mean PEF rate improved by 12%. At three months, the daytime asthma symptoms were reduced by 87%, and nighttime symptoms by 85%. The beta2-agonist use was reduced by 92% and the dose of corticosteroid inhaler was reduced by 84%. The mean PEF value increased by 15%. At one year, daytime symptoms of asthma were reduced by 94%, and nighttime symptoms by 95%. Beta2agonist use was reduced by 95%; the dose of corticosteroid inhaler was reduced by 92%. The mean PEF had increased by 18%. Finally, at three years, daytime symptoms of asthma were reduced by 97%, and nighttime symptoms by 98%. The dose of beta2agonist was reduced by 97%, and no patients took inhaled corticosteroids. The mean PEF had increased by 21%. At three years, nine of the 14 patients had achieved a symptom-free, medication-free, and asthma-free condition, in which they no longer developed asthma when exposed to the previous triggers of their asthma attacks. Ba and his colleagues conclude: “The excitatory modulator S. flavescens provided dramatic clinical and functional results for patients with moderate and severe asthma. We acknowledge that our study is open and selective, which might have led to a higher rate of success. However, the short-term and long-term multifaceted benefits of this treatment are not due to just a placebo effect. S. flavescens root extract, with a high content of matrine-type alkaloid, may target the causes of asthma more specifically compared with the available standard pharmaceutical therapies.”

TAKEAWAY

Ba feels that Sophora flavescens may reduce cell membrane excitability and markedly improve asthma, so that by the three-year mark, nine of twelve patients in this study were symptomfree and medication-free.

2010

Treating Asthma as a

Neuroelectrical Disorder17

This 2010 paper reviews the proposed excitatory model of asthma. Lung tissue has a rich bed of nerve circuits, and the epithelial, submucosal, and smooth muscle cells of the lung carry both voltage-gated sodium channels and glutamate receptors. Sodium influx stimulates the release of acetylcholine, causing smooth muscle contraction. There is a substantial body of evidence from basic research and clinical observations that indicate an important role of inducible and genetically predisposed airway membrane hyperexcitability in asthma pathogenesis and its relationship with emphysema and chronic lung disorders. The hyperexcitatory model of asthma pathogenesis may help to explain many unresolved issues of asthma’s pathology, epidemiology, clinical features, and therapeutic response. Ba and colleagues feel that modulation of membrane excitability may be found to

TAKEAWAY

Ba reviews the evidence that modulation of membrane excitability might be used for the management and prevention of asthma.

References

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2 Nakashima Y, Sugiyama S, Shindoh J, et al. Effects of sodium channel blockers on electrical field stimulation-induced guineapig tracheal smooth muscle contraction. Arch Int Pharmacodyn Ther. 1990;306:130-8. PMID: 1963767

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17 Hoang BX, Shaw DG, Pham P, et al. Treating asthma as a neuroelectrical disorder. Inflamm Allergy Drug Targets. 2010;9(2):130-4. PMID: 20359291