Historical perspectives on the discovery and development of drugs to treat neurological disorders

Abstract

Introduction Neurodegeneration is a key hallmark of most neurological diseases. These include Alzheimer's disease (AD, see Chapter 8; Ittner and Gotz 2011; Querfurth and LaFerla 2010), Parkinson's disease (PD, see Chapter 11; Meissner et al. 2011; Mounsey and Teismann 2011; Toulouse and Sullivan 2008), multiple sclerosis (MS, see Chapter 10; Peterson and Fujinami 2007), amyotrophic lateral sclerosis (ALS, see Chapter 12; Geser et al. 2009; Kiernan et al. 2011; Wijesekera and Leigh 2009), Huntington's disease (HD; Zuccato et al. 2010), and frontotemporal lobar degeneration (Rabinovici and Miller 2010). Neurodegeneration is also a major factor affecting the prognosis of stroke (Kleinschnitz et al. 2010), chronic pain (Reichling and Levine 2011), and epilepsy (Yang et al. 2008). Neurodegeneration has a multifactorial etiology with accumulating evidence across the various disease states for both genetic and environmental contributions (Coppede and Migliore 2009; Feany 2010). Although the diseases differ in regard to their postulated initiating events, which are multiple, complex, and largely unresolved, they may converge on common final pathway(s) that are triggered by the misfolding of key cellular proteins manifest as the amyloidopathies, tauopathies, a-synucleopathies, and TDP-43 proteinopathies (Geser et al. 2010). It remains unclear, however, whether protein misfolding is the initiating event for disease occurrence or is the result of other causes that include environmental factors such as toxins (Coppede and Migliore 2009); inflammation (Glass et al. 2010); oxidative stress (Lin and Beal 2006); mitochondrial dysfunction including apoptosis, autophagy/mitophagy (Choi et al. 2011; Correia et al. 2011; Johri et al. 2011; Keane et al. 2011; Mounsey and Teismann 2011; Readnower et al. 2011; Schapira 2007; Schon et al. 2010; Tranah 2011; Yang et al. 2008), and reduced ATP production (Volonte et al. 2003); ubiquitination (Chechanover and Brundin 2003; Huang and Figueiredo-Pereira 2009; Rogers et al. 2010); trauma; and impaired brain glucose/energy metabolism (Beal 2005; Choi et al. 2011; Correia et al. 2011; Johri et al. 2011; Keane et al. 2011; Liu et al. 2009). Thus, putative molecular targets based on both genome-wide association studies (GWAS) and postmortem assessment of brain pathology have not effectively distinguished between cause and effect, except in the case of HD (Zuccato et al. 2010), making the search for effective disease treatments problematic.