Clinical Trials for Neuroprotection in ALS

Abstract

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.

Oxidative stress modulation in neurodegenerative diseases

“…After 45 days of therapy, ALS patients showed during incremental exercise a significant decrease, compared to pre-treatment condition, of peak exercise blood AOPP levels and after 3 months therapy AOPP basal levels further significantly decreased compared to pre-treatment values. These results confirm the possible role of oxidative stress in sporadic ALS pathogenesis, at the same time underlining the beneficial effects of antioxidant cysteinedonor supplementation on biochemical markers of protein oxidation, especially during exercise [72].…”

“…We analyzed the modification of AOPP, FRAP and total GSH levels after each ceftriaxone cycle. Even if no clinical improvement has been evidenced, AOPP levels (increased in ALS patients compared to controls before therapy) significantly decreased in ALS treated patients, while total GSH and FRAP (significantly decreased in ALS patients compared to controls before therapy) showed a slight but not significant increment [72].…”

“…In particular, ceftriaxone, a cephalosporin of third generation that increases EAAT2 promoter activity and protects motor neurons from glutamate toxicity in vitro and in animal models [73], has been found to have antioxidant properties even if mainly negative clinical data have been described in limited ALS case-histories, published between 1992 and 1996 [72]. In our clinic we performed an open-label clinical trial in which we tested the effect of bimonthly drug cycles of ceftriaxone (2 g/day, for 14 days) within a planned 1-year study on 30 ALS patients.…”

The Multiple Faces of Valosin-Containing Protein-Associated Diseases: Inclusion Body Myopathy with Paget’s Disease of Bone, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis

“…One of the neuropathological hallmarks of ALS is the misfolding of proteins that may perturb a number of intracellular signaling and degradation pathways. The role of autophagy in sIBM and ALS pathogenesis has led to clinical trials such as lithium treatments (Crippa et al 2010a, b;Pasquali et al 2010;Siciliano et al 2010). …”

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

“…Of note, this inventory is neither comprehensive, nor does it contain all available references due to space restriction. It is mainly based on a selective literature search in the PubMed database, and summarizes recent reviews in the field (Carlesi et al, 2011;Miller et al, 2005;Siciliano et al, 2010;Zinman & Cudkowicz, 2011;Zoccolella et al, 2009). …”