Neurotrophic Factors and Amyotrophic Lateral Sclerosis

Abstract

The cause of motor neuron death in amyotrophic lateral sclerosis (ALS) remains a mystery. Initial implications of neurotrophic factor impairment involved in disease progression causing selective motor neuron death were brought forward in the late 1980s. These implications were based on several in vitro studies of motor neuron cultures in which a near to complete rescue of axotomized neonatal motor neurons in the presence of supplementary neurotrophic factors were revealed. These findings pawed the way for extensive investigations in experimental animal models of ALS. Neurotrophic factor administration in rodent ALS models demonstrated a remarkable effect on survival of degenerating motor neurons and rescue of axotomized motor neurons, both in vivo and in vitro. In the absence of efficient therapy for ALS, some of these promising neurotrophic factors have been administered to groups of ALS patients, as they appeared available for clinical trials. Up to date, none of tested factors has lived up to expectations, altering the outcome of the disease. This review summarizes current findings on neurotrophic factor expression in ALS tissue and these factors’ potential/debatable clinical relevance to ALS and the treatment of ALS. It also discusses possible interventions improving clinical trial design to obtain efficacy of neurotrophic factor treatment in patients suffering from ALS.

Immunohistochemical localization of insulin-like growth factor binding protein 2 in the central nervous system of SOD1G93A transgenic mice

“…Although several hypotheses have been postulated, the mechanisms whereby mutant SOD1 causes selective motor neuron death is not yet known (Rowland and Shneider 2001). Given that the striking pathological feature in ALS is motor neuron loss, many neurotrophic factors have been found to promote motor neuron survival in cell-culture models (Ekestern 2004). However, few have been found of benefit in the SOD1 mutant mice and all the clinical trials of such agents in ALS to date have been negative (Goodall and Morrison 2006).…”

Characterization of Meteorin—An Evolutionary Conserved Neurotrophic Factor

“…Furthermore, many of these factors may also be capable of repairing damaged neuronal populations in the adult and have therapeutic potential for disorders of the central nervous system, including Alzheimer's disease (Schindowski et al 2008), Parkinson's disease (Evans and Barker 2008), and amyotrophic lateral sclerosis (Ekestern 2004). Even though many important factors have been discovered and are under development as therapeutics, the discovery of novel neurotrophic growth factors such as conserved dopamine neurotrophic factor (Lindholm et al 2007) illustrates the continued importance of the discovery and detailed characterization of these types of molecules.…”

Cytoskeleton, Axonal Transport, and the Mechanisms of Axonal Neuropathy

“…Defective retrograde axonal transport from mutations of DCTN1 and DNCHC1 may lead to decreased neurotrophic support from the end organ-derived neurotrophic factors to related motor neurons. Deprivation of this neurotrophism has been proposed as a cause of cell death in the pathogenesis of ALS (Ekestern, 2004).…”