Millions of people around the world are affected by neurodegenerative diseases (ND). The two most common ND are Alzheimer’s disease (AD) and Parkinson’s disease (PD). According to 2016 statistics, in the US about 5.4 million people were afflicted by AD and in 2020 930,000 people are expected to live with PD.
Drug-induced neuropathic pain
Chronic oxidative stress/inflammation is known to induce neurodegenerative disorders such as the aforementioned Alzheimer’s disease (AD), Parkinson’s disease (PD), as well as Huntington’s disease (HD) (Kida 2010, Tabassum 2019, Jiao 2019). To date, there is no cure for these diseases.
The molecules of 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) comprise a seven-membered ring containing five sulfur atoms in a row. TC-2153, first synthesized — circa 2009 — at Russia’s Novosibirsk Institute of Organic Chemistry, is covered by patent RU0002672472 issued in 2018, and is being developed as an “antidepressant of new generation” by the research group of Alexander Kulikov (138,139). On the basis of preclinical studies in mice, Kulikov et al. were able to demonstrate that TC-2153 action is mediated by its effects on both the brain serotoninergic system and brain-derived neurotrophic factor (BDNF), which are known to be involved in the psychopathology of depression.
A few years ago, Paul Lombroso et al., at Yale University, identified TC-2153 as a potent inhibitor of phosphatase STEP, an enzyme that is overactive in several neuropsychiatric, neurodegenerative and ageing-related cognitive disorders, including Alzheimer’s disease (AD) and Huntington’s disease (HD).
Lombroso and his colleagues initially screened about 150,000 commercially available compounds, assessing their ability to inhibit STEP’s activity, toxicity, and ability to cross the blood-brain barrier: finally, eight good candidates emerged. Next, they synthesized the eight compounds “from scratch”, but it turned out that they possessed very little STEP inhibitory activity. Therefore, they considered the possibility that a “contaminant” present in the commercial lead compounds was inhibiting STEP activity, and discovered that, indeed, elemental alpha-sulfur was the active “contaminant”.
Lombroso et al. then looked for molecules structurally related to cyclooctasulfur, and “identified the benzopentathiepin core structure as the most promising one for further investigation”. Eventually they found that benzopentathiepin derivative TC-2153 had “reasonable aqueous solubility”, low acute toxicity (> 1,000 mg/kg), was able — upon parenteral administration — to cross the blood-brain barrier of mice, and inhibited STEP almost as potently as elemental alpha sulfur (S8).
These researchers employed the “triple transgenic” mouse model of AD, with mutations in genes known to cause this pathology (presenilin-1, amyloid precursor protein, and tau), to test the hypothesis that TC2153 could reverse some of the cognitive deficits due to STEP overactivity: in comparison with vehicle, intraperitoneal injection of TC-2153 significantly improved spatial working memory, novel object recognition, and reference memory.
The work of Kulikov’s group and the serendipitous discovery of Lombroso and his colleagues have had significant impact and might lead to the eventual development of a drug useful for treating depression, AD, HD, age-related cognitive impairment, schizophrenia and drug abuse, but — for the time being — their pioneering work has led to a better understanding of how depression and cognitive dysfunction originate and how they may be fought. In addition, their work has decisively contributed to open new avenues to develop drugs targeting a category of enzymes that for a long time had been considered undruggable.
Why is this story pertinent in the present context? Because it clearly shows that cyclooctasulfur (the main constituent of Sulfagenix's clinical-stage H2S prodrug, SG1002) is slightly more active against AD than the 150, 000 molecules assayed by Lombroso, including benzopentathiepin analogs. Furthermore, it may be hypothesized that the modes of action of SG1002 and TC-2153 against AD are identical and involve H2S as the key effector. In fact, it is known that H2S slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms (Xuan 2012, Liu 2016, He 2014, 2016; Giuliani 2013). This is highly significant because production of neuronal H2S is significantly decreased in patients with AD and increasing systemic H2S plasma levels diminish AD severity (He 2014).
The high potential therapeutic value of H2S against Parkinson’s disease is also well documented (Hu 2010, Jiao 2019, Tabassum 2019, Wang 2019, Paul 2018, Zhang 2014, Kida 2011).