Current Medicinal Chemistry - Volume 21, Issue 31, 2014

Amyotrophic Lateral Sclerosis (ALS) is a progressive, disabling neurodegenerative disorder characterized by progressive upper and lower motor neuron degeneration, leading to death from respiratory insufficiency after 3-5 years. ALS occurs either in familial (FALS; 10%) or sporadic (SALS; 90%) forms and its worldwide incidence ranges from 1.7 to 2.3 cases per 100,000 persons per year. Despite the identification of several disease-linked mutations, the etiology and pathogenesis of ALS are not well understood yet. The lack of adequate knowledge about molecular mechanisms involved in the neurodegenerative progression of ALS makes the development of effective treatments particularly difficult. Although several compounds showed promising results in preclinical studies in animal models, to date, there is no cure for ALS and the only FDA approved drug, Riluzole, has very modest efficacy on survival. A better approach to ALS therapy requires a better understanding of interactions between risk factors, pathophysiological mechanisms, biomarkers and phenotypic characteristics of patients. Thus, the aim of this special issue is to provide novel insights into both pathophysiological and pharmacological aspects of ALS. Pasquali et al. focus on the altered autophagy pathways and on the consequent formation of misfolded proteins, emphasizing the cell-to-cell protein propagation as therapeutic target in ALS. Finally, the authors discuss cell replacement therapy with focal stem cells implantation. Menon et al. discuss the role of glutamate-mediated excitotoxicity, upregulation of axonal voltage-gated persistent Na+ channel and mitochondrial dysfunction and genetic factors in ALS pathogenesis. A potential approach involving the use of antisense oligonucleotide as genetic therapy is also discussed. The main topic of the paper by Blasco et al. is excitotoxicity in ALS. The authors focus on the events implicated in this process and summarize clinical trials with drugs targeting the glutamate system, and discuss their potential role as biomarkers. The review by Lee et al. deals with therapeutic targeting of epigenetic components in ALS. The authors, in particular, point out the use of Histone Deacetylases Inhibitors (HDAC) as candidate drugs to treat disorders such as ALS. The paper by Yacila and Sari details the role of potential biomarkers identified until today and the potential role of neurotrophic peptides, drugs, stem cell therapy and immunotherapy as promising strategies for the treatment of ALS. Taken together, the reviews published in the present special issue of CMC provide the reader an extensive overview of recent findings regarding molecular mechanisms involved in ALS, emphasizing the importance of these processes as potential biomarkers and therapeutic targets and highlighting new perspectives for drug development.

Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid cellto- cell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas.

Although the pathophysiological mechanisms underlying the development of amyotrophic lateral sclerosis (ALS) remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. Glutamate- mediated excitoxicity is an important pathophysiological pathway in ALS, and was identified as an important therapeutic biomarker leading to development of the only pharmacologically based disease-modifying treatment currently available for ALS. More recently, a putative role of voltage-gated persistent Na+ channels in ALS pathogenesis has been suggested and underscored by neuroprotective effects of Na+ channel blocking agents in animal models. In addition, advances in ALS genetics have lead to identification of novel pathophysiological processes that could potentially serve as therapeutic targets in ALS. Genetic therapies, including antisense oligonucleotide approaches have been shown to exert neuroprotective effects in animal models of ALS, and Phase I human trial have been completed demonstrating the feasibility of such a therapeutic approach. The present review summarises the advances in ALS pathogenesis, emphasising the importance of these processes as potential targets for drug development in ALS.

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs.

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by degeneration of motor neuron and glial activation followed by the progressive muscle loss and paralysis. Numerous distinct therapeutic interventions have been examined but currently ALS does not have a cure or an efficacious treatment for the disorder. Glutamate- induced excitotoxicity, inflammation, mitochondrial dysfunction, oxidative stress, protein aggregation, transcription deregulation, and epigenetic modifications are associated with the pathogenesis of ALS and known to be therapeutic targets in ALS. In this review, we discuss translational pharmacological studies targeting epigenetic components to ameliorate ALS. Understanding of the epigenetic mechanisms will provide novel insights that will further identify potential biological markers and therapeutic approaches for treating ALS. A combination of treatments that modulate epigenetic components and multiple targets may prove to be the most effective therapy for ALS.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder caused by damage of motoneurons leading to paralysis state and long term disability. Riluzole is currently the only FDA-approved drug for the treatment of ALS. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, protein aggregation, SOD1 accumulations, and neuronal death. In this review, we discuss potential biomarkers for the identification of patients with ALS. We further emphasize potential therapy involving the uses of neurotrophic factors such as IGFI, GDNF, VEGF, ADNF-9, colivelin and angiogenin in the treatment of ALS. Moreover, we described several existing drugs such as talampanel, ceftriaxone, pramipexole, dexpramipexole and arimoclomol potential compounds for the treatment of ALS. Interestingly, the uses of stem cell therapy and immunotherapy are promising for the treatment of ALS.

The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system’s primary function in leukocyte migration, it has a central role in immune homeostasis and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity-contributing interactions are attributed to different domains and known to occur in two steps. Here, knowledge on chemokine and receptor domains involved in the first binding-step and the second activation-step is reviewed. A mechanism comprising at least two steps seems consistent; however, several intermediate interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly interact with or rely on transmembrane receptor residues, while CXC-chemokines use residues located further exterior. Moreover, different chemokines for the same receptor often bind at different sites, uncovering the existence of several orthosteric sites thereby adding another level of complexity. This gives rise to a probe-dependency of small molecule “drug-like” ligands, which, depending on the chemokine interaction, may bind allosteric for some, and orthosteric for other chemokines targeting the same receptor, thereby resulting in probedependent pharmacodynamics.