ALSUntangled 46: penicillin G/hydrocortisone

Abstract

Penicillin G (benzylpenicillin; PNG) is a natural member of the b-lactam class of antibiotics which today is most often used against syphilis and susceptible Streptococcus infections (2). PNG has been reported to decrease the effect of the inhibitory neurotransmitter GABA (Ç-aminobutyric acid) in vitro (3) through inhibition of GABA receptors (4–7), inhibition of GABA molecular synthesis (8), and inhibition of GABA synaptic release (9,10). PNG may also decrease excitotoxicity caused by the neurotransmitter glutamate as described below. Hydrocortisone (HC; cortisol) is the main glucocorticoid steroid that humans produce naturally in the adrenal glands. Glucocorticoids have many actions, most of which are either metabolic or immunologic. Glucocorticoids are anti-inflammatory and immunosuppressive. Synthetic glucocorticoids and HC are used in medicine for many endocrine, autoimmune, and inflammatory disorders (11). HC can also affect GABA neurotransmission in vitro and in healthy humans (12–14). In a case series published in 1990, PNG and HC were used to treat five patients with blood tests positive for syphilis and a motor neuron disease resembling ALS (15). Four of these patients subsequently had improved strength and/or function that was maintained through an approximately 5-year follow-up. The fifth had stability of their ALS-like illness through 10-years of follow-up. Since this is not typical of the natural history of ALS, the authors concluded that neurosyphilis could manifest as a potentially treatable ALS-mimic syndrome. Recently, Dr. Bert Tuk, a pharmacology researcher, hypothesized an alternate explanation for the treatment-associated benefits seen in these five patients: that the combination of PNG actions on GABA and HC actions on GABA and neuroinflammation were responsible, while the syphilis infection was only coincidental (16–18). Tuk has applied for a patent to use GABA inhibitors in ALS which includes the PNG/HC regimen (19); he is the founder of Ry Pharma, a company developing GABA inhibitor pharmaceuticals with plans for a future clinical trial (20). We review Dr. Tuk’s hypotheses in the “Mechanisms” section. Tuk has also published a case series of three PALS without syphilis who were treated with combination intravenous PNG and HC (21), which we will discuss in the “Cases” section.