Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article)

Salah Mohamed El Sayed*, Elsayed Abdelkreem, Moutasem Salih Aboonq, Sultan S. Al Thagfan, Yaser M. Alahmadi, Osama Alhadramy, Hussam Baghdadi, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa Abdel-ziz, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf, Manal Mohamed Helmy Nabo

Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

Abstract: Beta-ketothiolase deficiency (BKTD) is an inborn error of ketone bodies and isoleucine metabolism. Patients with BKTD manifest during late infancy and early childhood with recurrent episodes of ketoacidosis (accumulated acetoacetate and β-hydroxybutyrate) that may be refractory to treatment and life-threatening. BKTD is exaggerated by fasting, starvation and catabolic conditions. Dichloroacetate (DCA) is a safe effective treatment for both lactic acidosis and non-Hodgkin’s lymphoma. DCA is non-toxic and non-carcinogenic at therapeutic doses. DCA toxic doses are hundred times (12- gram/l) more than the therapeutic doses. In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose. Importantly, DCA was reported to divert pyruvate (amino group acceptor to form alanine in transamination reactions to regenerate α-ketoglutarate from glutamate) to oxidative pathways to form acetyl CoA that is oxidized in Krebs cycle. That inhibits first step of isoleucine catabolism (transamination step) and consequently blocks formation of acetoacetate and β-hydroxybutyrate. That alleviates ketone bodies-induced refractory metabolic acidosis. On biochemical and pharmacological bases, we suggest DCA as a novel evidence-based adjuvant and life-saving treatment for BKTD. Moreover, DCA-induced inhibition of ketone bodies uptake will be alleviated by insulin effects. Causes of refractory metabolic acidosis in BKTD are increased levels of ketone bodies (due to increased isoleucine catabolism, increased ketone bodies formation and decreased ketone bodies utilization). DCA relieves most of these. Biochemically, DCA and ketone bodies (acetoacetate and β-hydroxybutyrate) are structural analogs derived from acetic acid. In neonatology, DCA improved neonatal septicaemia-induced refractory metabolic acidosis that did not respond to conventional sodium bicarbonate. In conclusion, DCA is strongly suggested to treat BKTD.

Keywords: Dichloroacetate, beta-ketothiolase deficiency, antimetabolite, pharmacological antagonist, ketone bodies, acidosis, isoleucine

Received December 02, 2019; Revised January 06, 2020; Accepted March 08, 2020

Citation: Salah Mohamed El Sayed, Elsayed Abdelkreem, Moutasem Salih Aboonq, Sultan S. Al Thagfan, Yaser M. Alahmadi, Osama Alhadramy, Hussam Baghdadi, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa Abdel-ziz, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf, Manal Mohamed Helmy Nabo, Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article). International Journal of Clinical and Experimental Neurology, 8 (1). 4-8. January 2020. doi:10.12691/ijcen-8-1-2

1. Introduction

Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase [T2]; EC 2.3.1.9; encoded by ACAT1 gene) is a vital enzyme for ketone bodies and isoleucine metabolism [1]. Beta-ketothiolase deficiency (BKTD) is a rare autosomal recessive disorder characterized by an inborn error of isoleucine catabolism and affecting ketone body metabolism. Its clinical features are characterized by intermittent ketoacidotic episodes that are associated with clinical signs and symptoms of toxic encephalopathy e.g. lethargy, hypotonia, vomiting, tachypnea, and coma in some patients, with an onset during infancy or toddlerhood [2].

In ketone bodies synthesis in the liver, T2 catalyzes the formation of acetoacetyl-CoA from two acetyl-CoA molecules. In extrahepatic ketone body utilization, T2 is responsible for the thiolytic cleavage of acetoacetyl-CoA into two molecules of acetyl-CoA (Figure 1) [1]. In isoleucine catabolism, T2 catalyzes the thiolysis of 2-methylacetoacetyl-CoA to acetyl-CoA and propionyl-CoA (a glucogenic substrate) (Figure 2). Branched-chain aminotransferase catalyzes the first reaction in the catabolic pathway of branched-chain amino acids, a reversible transamination that converts branched-chain amino acids into branched-chain ketoacids [3] (Figure 3).

Figure 1. Role of β-ketothiolase in ketone bodies synthesis (ketogenesis) and oxidation. DCA can prevent ketogenesis and inhibit further isoleucine catabolism (minimizing further acetoacetate formation and related ketoacidosis)

Figure 2. Biochemical bases and consequences of β-ketothiloase (BKT) deficiency. BKT plays a vital role in catabolism of isoleucine. BKT cleaves methylacetoacetyl CoA into acetyl CoA and propionyl CoA. Deficiency of BKT results in the accumulation of acetoacetate and lack of ketone bodies utilization. Fortunately, 1st step of isoleucine catabolism (transamination step) is reported to be indirectly inhibited by dichloroacetate (DCA). DCA inhibits first step of isoleucine catabolism preventing ketone bodies formation and subsequent refractory metabolic acidosis. That may suggest a promising role of DCA in treating BKT deficiency.

Figure 3. Transamination of isoleucine is vital for its catabolism. Alanine aminotransferase (ALT, GPT). The reaction is readily reversible. However, during amino acid catabolism, ALT enzyme functions in the direction of glutamate synthesis

Beta-ketothiolase deficiency (BKTD; MIM# 203750, 607809) is an inborn error of ketone body and isoleucine metabolism. Patients with BKTD usually manifest during late infancy and early childhood with recurrent episodes of ketoacidosis. A history of ketogenic triggers e.g. prolonged fasting, febrile illness and/or high protein intake is usually present. Frequency and severity of ketoacidotic episodes vary among patients. A considerable proportion of patients develop severe episode/s, commonly with encephalopathy and/or hemodynamic collapse. Death or permanent neurological abnormalities (e.g., gait/movement disorders, hypotonia, and mental retardation) are well-documented possible complications [4]. Based on that, in ketoacidoses of BKTD, source ketone bodies are both fatty acids catabolism and impaired isoleucine catabolism.

In addition, some patients with BKTD may develop chronic neurological impairment (mainly extrapyramidal manifestations) independent of the frank ketoacidosis. This could be attributed to accumulated isoleucine catabolic metabolites (particularly 2-methylactoacetate and 2-methyl 3-hydroxybutyrate) (Figure 2). Therefore, BKTD should be considered not only as a defect in ketone body utilization but also as a defect in isoleucine catabolism with the potential for insidious cerebral toxicity [1]. Strategies for treating BKTD should include reducing metabolic acidosis, inhibiting ketogenesis, stimulating ketone bodies utilization, inhibiting lactate formation (anerobic metabolism), relieving metabolic effects exerted by the accumulated ketones (acetoacetate and β-hydroxybutyrate), and decreasing isoleucine catabolism (Figure 2) [1,2,3,4]. Most of these may be achieved using the acetate analog dichloroacetate (DCA).

Figure 4. Some acetate derivatives of biological importance. Acetyl CoA, acetoacetate, β-hydroxybutyrate and dichloroacetate (DCA) are acetate analogs. An evident pharmacological antagonism was reported between acetate and DCA. An evident pharmacological antagonism was reported between ketone bodies and DCA as regard effects on arterial blood pH where DCA treats metabolic acidosis

DCA is a derivative of acetic acid by replacing two hydrogen atoms by two chloride atoms (Figure 4). There is no evidence or report that therapeutic doses of DCA are carcinogenic or toxic. DCA is quite safe at therapeutic doses. Biochemically, both DCA and ketone bodies (acetoacetate and β-hydroxybutyrate) are structural analogs derived from acetic acid (Figure 4).

Table 1. Key clinical features of beta-ketothiolase (BKT, T2) deficiency [1]

2. The Hypothesis/Theory

1. On biochemical and pharmacological bases and in light of a previous report [5], we hypothesize that DCA is a promising adjuvant treatment (with insulin/glucose) for treating BKTD. That is because DCA inhibits isoleucine catabolism upstream of the step catalyzed by beta-ketothiolase (before formation of acetoacetyl-CoA). Hence, DCA participates in decreasing the formation of (1) isoleucine catabolic intermediates, which are neurotoxic, thereby decreasing the incidence of chronic neurological impairment and (2) acetyl-CoA is the precursor of ketogenesis, thereby decreasing ketoacidosis.

2. DCA decreases lipolysis and serum free fatty acids [6]. It is well-known that oxidation of free fatty acids gives acetyl-CoA that is the main source for ketogenesis in the liver. Therefore, DCA decrease ketone body production and consequently decreases the severity of BKTD.

3. DCA is an antimetabolite of acetate (precursor of ketogenesis) [7], acetoacetate (ketone body) and β-hydroxybutyrate (ketone body) [8]. Thus DCA decreases ketone bodies formation (through antagonizing acetate).

4. Being a structural analog to acetate and ketone bodies (acetoacetate and β-hydroxybutyrate), DCA may act as a pharmacological antagonist to ketone bodies i.e. DCA will alleviate the refractory metabolic acidosis induced by ketone bodies accumulation [9] due to BKTD and other causes.

5. Based on that, DCA is promising as a sole treatment (or adjuvant treatment to insulin/glucose) for treating BKTD in acute episodes as well as a long-term prophylaxis for potential chronic neurological impairment.

3. Evaluation of the Hypothesis/Theory

In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose [10]. DCA inhibits alanine formation (from pyruvate) through activating pyruvate oxidation to form acetyl CoA to start Krebs cycle and other metabolic pathways. This decreases pyruvate transamination to form alanine. That secondarily disturbs branched-chain amino acid transamination (by limiting the amino group acceptors necessary to form alanine in transamination reactions to regenerate α-ketoglutarate from glutamate). α-ketoglutarate is essential for isoleucine transamination and subsequent catabolism (Figure 3) [5]. This is supported by the report that DCA increases lactate/pyruvate ratio [11]. This minimizes pyruvate availability for transamination of branched chain amino acids and inhibits their further catabolism i.e. decreases the severity of BKTD.

Blackshear et al. reported a marked decrease in the concentration of ketone bodies (acetoacetate and β-hydroxybutyrate) after DCA treatment to rats where DCA inhibited the production of ketone bodies during severe ketoacidosis [12]. That was supported by another report where DCA infusion induced a maximal decrease in serum ketone bodies (acetoacetate and β-hydroxybutyrate) after a prior small increase [12]. Interestingly, DCA did not affect insulin-induced serum clearance of ketone bodies [12].

4. Evidences that DCA Antagonizes Ketone Bodies Effects Particularly Acidosis

DCA inhibits extrasplanchnic ketone bodies uptake evidenced by DCA-induced inhibition of β-hydroxybutyrate oxidation by rat diaphragm muscle [9]. That was supported by DCA-induced increase in serum ketone bodies [12,13].

Table 2. Evidences that DCA is strongly suggested for treating BKTD

5. Empirical Data

DCA and ketone bodies are structural analogs to acetate. This may suggest competing effects and pharmacological antagonism between DCA and ketone bodies. This is evidenced by the report that infusion of DCA into rats with severe diabetic ketoacidosis over four hours caused a marked decrease in blood ketone bodies concentration [12,13]. Recently, Being an analog of acetate (precursor of ketogenesis), DCA was recently suggested as a competitive inhibitor of ketogenesis and ketone bodies effects [8]. DCA was reported to significantly decrease ketone bodies formation [13] and antagonize acetate [7]. In experimental models of ketosis, DCA reduced ketonemia and ketonuria while significantly decreased blood glucose. However, DCA inhibited peripheral ketone bodies uptake and did not increase ketone bodies utilization [12,13], which can be minimized upon combining DCA with insulin/glucose.

6. Consequences of the Hypothesis/Theory

Table 3. Therapeutic benefits of DCA for treatment of BKTD

7. Conclusion

Our hypotheses carry a lot of hope in introducing DCA as a novel potential promising and life-saving adjuvant treatment to glucose/insulin for treating BKTD and related metabolic disorders through alleviating the refractory acidosis and progressive metabolic derangements following isoleucine catabolism and related ketosis.

Conflict of Interest

The authors declare that there is no conflict of interest

Financial Support

The authors declare that they did not receive any financial support from any source for this research article.

References

[1]   | Fukao T, Sasai H, Aoyama Y, Otsuka H, Ago Y, Matsumoto H, Abdelkreem E. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet. 2019 Feb; 64(2): 99-111.
[2]   | Vakili R, Hashemian S. A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature. Iran J Child Neurol. 2018 Summer; 12(3): 113-121.
[3]   | Adeva-Andany MM, López-Maside L, Donapetry-García C, Fernández-Fernández C, Sixto-Leal C. Enzymes involved in branched-chain amino acid metabolism in humans. Amino Acids. 2017 Jun; 49(6): 1005-1028.
[4]   | Reddy N, Calloni SF, Vernon HJ, Boltshauser E, Huisman TAGM, Soares BP. Neuroimaging Findings of Organic Acidemias and Aminoacidopathies. Radiographics. 2018 May-Jun; 38(3): 912-931.
[5]   | Snell K, Duff DA. Branched-chain amino acid metabolism and alanine formation in rat diaphragm muscle in vitro. Effects of dichloroacetate. Biochem J. 1984 Nov 1; 223(3): 831-5.
[6]   | Ward RA, Wathen RL, Harding GB, Thompson LC. Comparative metabolic effects of acetate and dichloroacetate infusion in the anesthetized dog. Metabolism. 1985 Jul; 34(7): 680-7.

[7]  
El Sayed SM, Baghdadi H, Ahmed NS, Almaramhy HH, Mahmoud AA, El-Sawy SA, Ayat M, Elshazley M, Abdel-Aziz W, Abdel-Latif HM, Ibrahim W, Aboonq MS. Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis. Med Hypotheses. 2019 Jan; 122: 206-209.

[8]   | Ayat M. Dichloroacetate is Promising for Treating Hematological Malignancy through Inhibiting Ketone Bodies Oxidation: towards Better Understanding of Its Anticancer Mechanisms. American Journal of Cancer Prevention. 2018, 6(1), 5-8.

[9]  
McAllister A, Allison SP, Randle PJ. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. Biochem J. 1973 Aug; 134(4): 1067-81.

[10]   | Stacpoole PW, Greene YJ. Dichloroacetate. Diabetes Care. 1992 Jun; 15(6):785-91.
[11]   | Pardridge WM, Duducgian-Vartavarian L, Casanello-Ertl D. Effects of dichloroacetate on the lactate/pyruvate ratio and on aspartate and leucine metabolism in cultured rat skeletal muscle cells. Biochem Pharmacol. 1983 Jan 1; 32(1): 97-100.
[12]   | Backshear PJ, Holloway PA, Alberti KG. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J. 1975 Feb; 146(2): 447-56.
[13]   | Blackshear PJ, Holloway PA, Alberti KG. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J. 1974 Aug; 142(2): 279-86.
[14]   | Graf H, Leach W, Arieff A I. Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs. J Clin Invest. 1985 Sep; 76(3): 919-923.
[15]   | Gin-Shaw SL, Barsan WG, Eymer V, Hedges J. Effects of dichloroacetate following canine asphyxial arrest. Ann Emerg Med. 1988 May; 17(5): 473-7.
[16]   | James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther. 2017 Feb; 170: 166-180.