Mitochondrial dysfunction in amyotrophic lateral sclerosis – a valid pharmacological target?

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression.

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This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Evaluation of the oral direct factor Xa inhibitor – betrixaban

Introduction: Mineral and bone disorder (MBD) begins early in the course of chronic kidney disease (CKD). Phosphate imbalance in CKD-MBD can lead to various pathologies of clinical importance such as further deterioration of kidney function, cardiovascular complications, renal osteodystrophy and increased mortality.

Areas covered: The authors conducted a systematic review of the biomedical literature to evaluate currently available drugs and new phosphate binder therapeutics in development.

Expert opinion: There is a need to continue searching for novel phosphate binders that better match an ‘ideal’ product profile. This profile should have: i) a product that is highly efficient in binding phosphate; ii) low patient compliance issues; iii) minimal interaction with other drugs; and iv) reduced side effects and safety concerns. Targeting alternative mechanisms, such as developing inhibitors for intestinal type II sodium-dependent phosphate co-transporter, may also improve the limitations of phosphate binder therapeutics. Current medical practice focuses on using serum phosphorus levels as the only marker for detecting, monitoring and treating phosphate imbalance in CKD. However, the consequences of phosphate imbalance are evident in non-dialysis patients before serum phosphate levels rise above the normal range. There is a need to search for other markers to guide detection and treatment of clinically significant alterations in phosphate metabolism of non-dialysis CKD.     

B-cell activating factor (BAFF) — a new factor linking immunity to diet?

B cell activation factor (BAFF) is a recently discovered member of the TNF ligand superfamily secreted by adipocytes, previously linked to autoimmune and lymphoproliferative disease. The aim of this study was to investigate the relationship between BAFF plasma levels and the non-modified, usual dietary composition as well as obesity-related anthropometric parameters in a cohort of 58 obese and non-obese Central-European Caucasian individuals. We found that BAFF had an independent predictive role for percentage of body fat; moreover, BAFF levels were correlated with waist and hip circumference. BAFF plasma levels were also significantly correlated with investigated dietary composition based on the 7-day food records, as the BAFF levels correlated with the percentage of energy derived from the carbohydrates and with energy derived from the dietary fat. Our results suggest that BAFF may play a role in linking the immune status and metabolic response to diet.     

An immune gate of depression – Early neuroimmune development in the formation of the underlying depressive disorder

The prevalence of depression worldwide is increasing from year to year and constitutes a serious medical, economic and social problem. Currently, despite multifactorial risk factors and pathways contributing to depression development, a significant aspect is attributed to the inflammatory process. Cytokines are considered a factor activating the kynurenine pathway, which leads to the exhaustion of tryptophan in the tryptophan catabolite (TRYCAT) pathway. This results in the activation of potentially neuroprogressive processes and also affects the metabolism of many neurotransmitters.The immune system plays a coordinating role in mediating inflammatory process. Beginning from foetal life, dendritic cells have the ability to react to bacterial and viral antigens, stimulating T lymphocytes in a similar way to adult cells. Cytotoxicity in the prenatal period shapes the predisposition to the development of depression in adult life. Allostasis, i.e. the ability to maintain the body’s balance in the face of environmental adversity through changes in its behaviour or physiology, allows the organism to survive but its consequences may be unfavourable if it lasts too long.As a result, Th lymphocytes, in particular T helper 17 cells, which play a central role in the immunity of the whole body, contribute to the development of both autoimmune diseases and psychiatric disorders including depression, as well as have an impact on the differentiation of T CD4+ cells into Th17 cells in the later development of the child’s organism, which confirms the importance of the foetal period for the progression of depressive disorders.     

Is impaired flow-mediated dilatation of the brachial artery a cardiovascular risk factor?

Endothelial dysfunction is thought to be an important factor in the development of atherosclerosis. Over the past decade, a non-invasive technique has evolved to evaluate flow-mediated vasodilation ([FMD), an endothelium-dependent function, in the brachial artery. FMD decreases with increasing age and subjects with diabetes mellitus, hypercholesterolemia, smokers and hypertension have decreased FMD. There are a few concise studies reporting that FMD predicts cardiovascular events. However, the assumption that focal measurement of brachial artery FMD predicts coronary artery disease deserves further investigation.     

The fall and rise of pharmacology – (Re-)defining the discipline?

Pharmacology is an integrative discipline that originated from activities, now nearly 7000 years old, to identify therapeutics from natural product sources. Research in the 19th Century that focused on the Law of Mass Action (LMA) demonstrated that compound effects were dose-/concentration-dependent eventually leading to the receptor concept, now a century old, that remains the key to understanding disease causality and drug action. As pharmacology evolved in the 20th Century through successive biochemical, molecular and genomic eras, the precision in understanding receptor function at the molecular level increased and while providing important insights, led to an overtly reductionistic emphasis. This resulted in the generation of data lacking physiological context that ignored the LMA and was not integrated at the tissue/whole organism level. As reductionism became a primary focus in biomedical research, it led to the fall of pharmacology. However, concerns regarding the disconnect between basic research efforts and the approval of new drugs to treat 21st Century disease tsunamis, e.g., neurodegeneration, metabolic syndrome, etc. has led to the reemergence of pharmacology, its rise, often in the semantic guise of systems biology. Against a background of limited training in pharmacology, this has resulted in issues in experimental replication with a bioinformatics emphasis that often has a limited relationship to reality. The integration of newer technologies within a pharmacological context where research is driven by testable hypotheses rather than technology, together with renewed efforts in teaching pharmacology, is anticipated to improve the focus and relevance of biomedical research and lead to novel therapeutics that will contain health care costs.     

β-Lactamase inhibitors: a review of the patent literature (2010 – 2013)

Introduction: New β-lactamases with ever-broadening substrate specificity are rapidly disseminating globally, thereby threatening the efficacy of our best β-lactam antibiotics. A potential solution to this problem is the development of wide-spectrum β-lactamase inhibitors, to be coadministered with existing and new β-lactams.

Areas covered: This review covers the patent literature in the β-lactamase inhibitor area roughly from 2010 to 2013, with prior background being provided in the cases of key inhibitors and antibiotic/inhibitor combinations. An effort has been made to identify the strong and weak points of each inhibitor and combination.

Expert opinion: Research in this field has become increasingly diverse, with several non-β-lactam inhibitor classes now assuming importance. The emphasis has been on finding inhibitors of AmpC, the extended-spectrum β-lactamases and class A and D carbapenemases that can demonstrate synergy with antibiotics against resistant Gram-negative pathogens. Progress has been made. Metallo-β-lactamases (MBL)-mediated resistance, however, represents an unmet challenge. The author believes that it will be extremely difficult to generate a selective, commercially viable MBL inhibitor with sufficient activity against NDM-1 and that alternate design strategies will need to be employed.     

Priapism – a review of the medical management

Priapism is characterised by the presence of prolonged, often painful penile erection in the absence of a sexual stimulus. This rare condition has a range of aetiologies, but is most common following self-administration of injection therapy for impotence. Priapism may be classified into high- and low-flow states. Low-flow priapism is an emergency ischaemic condition requiring prompt recognition and treatment to avoid devastating long-term complications of erectile dysfunction. Wide-ranging medical therapies are covered in this review. Diagnostic and treatment algorithms are suggested in light of the current available literature.     

Inducible tyrosine kinase inhibitors: a review of the patent literature (2010 – 2013)

Introduction: The non-receptor tyrosine kinase, inducible tyrosine kinase (Itk), plays an important role in thymus(T)-cell signalling and the production of pro-inflammatory cytokines. Itk, and the other Tec family members, Rlk and Tec, are viewed as attractive drug targets for new agents for the treatment of autoimmune and inflammatory diseases. Interest in Itk inhibitors is still modest compared to other kinases such as the Janus kinase (JAK) family or Syk.

Areas covered: This article reviews the patent filings published from January 2010 to April 2014 that claim Itk inhibitors. It first considers those applications that claim selective, or apparently selective, Itk inhibitors. It then considers those applications that claim less-selective Itk inhibitors. The recent interest in irreversible Itk inhibitors is also discussed.

Expert opinion: There is a difference of opinion as to the preferred utility for Itk inhibitors. Progress has been made in designing selective Itk inhibitors but little clinical progress. Until clinical data are available, it remains difficult to assess how well Itk inhibitors compare with JAK inhibitors as potential treatments for rheumatoid arthritis. However, animal data suggest that irreversible Itk inhibitors could be useful in treating asthma, whereas dual Itk inhibitors may have more utility in treating rheumatoid arthritis.     

Mitochondrial toxicity of the phyotochemicals daphnetoxin and daphnoretin – Relevance for possible anti-cancer application

Daphnetoxin is a daphnane type orthoester diterpene found exclusively in plants of the family Thymelaeaceae while daphnoretin, a bis-coumarin derivative that is the major constituent of the bark of some plants of this family, can also be found in Leguminosae and Rutaceae. These two compounds are recognized to have different biological effects, including a possible anti-cancer activity. The subject of the present research was to compare their mitochondrial toxicity and also investigate a possible selectivity towards tumor cell lines. Wistar rat liver mitochondria and three distinct cell lines were used to investigate compound-induced toxicity. The results indicate that both test compounds are toxic to isolated mitochondrial fractions, especially when used at concentrations higher than 100 μM. However, daphnetoxin presented the highest toxicity including increased proton leak in the inner mitochondrial membrane, increased induction of the mitochondrial permeability transition pore, inhibition of ATP synthase and inhibition of the mitochondrial respiratory chain. Both compounds also inhibited cell proliferation, regardless of the cell line used. Up to the maximal concentration tested in cells, no mitochondrial effects were detected by vital epifluorescence imaging, indicating that inhibition of cell proliferation may also originate from mitochondrial-independent mechanisms. The results warrant careful assessment of toxicity vs. pharmacology benefits of both molecules.     

Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

Drug‐induced liver injury (DILI) is poorly predicted by single‐cell‐based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver‐specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose–response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug‐induced hepatotoxicity was assessed with hepatotoxicants and non‐hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non‐hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI. Copyright © 2015 John Wiley & Sons, Ltd.     

Tavaborole – a treatment for onychomycosis of the toenails

Introduction: Onychomycosis is a fungal nail infection that accounts for half of all nail diseases. Oral drugs on the market have adverse effects, while it is difficult for traditional topical drugs to penetrate the nail plate to reach the diseased nail bed. Tavaborole is a new drug that addresses the unmet needs of currently available treatments. Tavaborole (5%) is FDA approved for treating toenail onychomycosis and has shown antifungal activities against yeast, moulds and dermatophytes.

Areas covered: The objective of this article is to review the efficacy, pharmacokinetics, pharmacodynamics, and safety of tavaborole for treatment of toenail onychomycosis.

Expert commentary: Tavaborole, with its unique mechanism, may be a good candidate for use in treating children with fungal infections, diabetic individuals, and treating mixed infections. Tavaborole may be paired with other therapies to potentially increase cure rates.     

Treatment of idiopathic generalized epilepsy – a review of the evidence

Introduction: Epilepsy is stratified into idiopathic partial, symptomatic partial, idiopathic generalized (IGE) and symptomatic generalized epilepsies.

Areas covered: The epidemiology and clinical characteristics of IGE are reviewed in this paper. Clinically, IGE is characterized by the occurrence of any of the following three seizure types: absence seizures, myoclonic seizures and primarily generalized tonic-clonic seizures. To assess the presence of evidence-based data on the treatment of IGE, the literature was extensively reviewed for studies evaluating the treatment of IGE with various antiepileptic drugs. These studies were stratified into four classes based on recently described criteria. Class I studies were considered as providing evidence of the efficacy of the drug in patients with IGE. Finally, suggestions to evaluate the efficacy of a study drug in patients with IGE are presented.

Expert opinion: Based on the reviewed data, there is strong evidence-based data to support the use of valproate and ethosuximide for the treatment of childhood absence seizures; for the use of topiramate as monotherapy or adjunctive therapy for patients with primarily generalized tonic-clonic seizures; for the use of adjunctive therapy with lamotrigine for the treatment of primarily generalized tonic-clonic seizures; and for the use of levetiracetam as adjunctive therapy for the treatment of myoclonic or primarily generalized tonic-clonic seizures. To evaluate a new drug as a potential treatment for patients with IGE requires a rational methodology, discussed in this review.