ABSTRACT
The access of drugs into the central nervous system (CNS) is regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). A large body of evidence supports perturbation of these barriers in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Modifications to the BBB and BSCB are also reported in amyotrophic lateral sclerosis (ALS), albeit these modifications have received less attention relative to those in other neurodegenerative diseases. Such alterations to the BBB and BSCB have the potential to impact on CNS exposure of drugs in ALS, modulating the effectiveness of drugs intended to reach the brain and the toxicity of drugs that are not intended to reach the brain. Given the clinical importance of these phenomena, this review will summarise reported modifications to the BBB and BSCB in ALS, discuss their impact on CNS drug exposure and suggest further research directions so as to optimise medicine use in people with ALS.
Introduction
Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease in adults, leading to muscle weakness and eventual paralysis and respiratory failure. ALS typically occurs in late middle life (51-66 years), with an incidence of 0.6-3.8 per 100 000 person-years and a prevalence of 4.1-8.4 per 100 000 persons (Longinetti & Fang, 2019). Despite affecting individuals for more than 150 years, this progressive neurodegenerative and fatal disease has limited treatment options, with riluzole and edaravone being the only two United States Food and Drug Administration-approved treatment options (Shefner et al., 2020). The majority of individuals with ALS can survive 3-5 years after appearance of symptoms, despite being administered riluzole (Chiò et al., 2009). ALS is mainly a sporadic disease with about 10% of cases being familial in nature (Chiò et al., 2009). Multiple factors contribute to the pathogenesis of ALS, including dysfunctional RNA metabolism, defective protein homeostasis, mitochondrial dysfunction, oxidative stress, neuroinflammation, and vesicular transport defects (Mejzini, Flynn, Pitout, Fletcher, Wilton & Akkari, 2019).
Despite a wealth of research being undertaken to reverse the pathology associated with ALS, translating this to ALS therapeutics has not been very successful. While there are multiple reasons for preclinical-to-clinical failure for ALS therapeutics, including heterogeneity of ALS pathology (Beghi et al., 2007) and species differences in efficacy, a major reason as to why many CNS candidates fail to reach the market is their inability to reach their site of action within the brain, due to the defence nature of the CNS barriers (Nicolazzo, Charman & Charman, 2006). These barriers, including the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), consist of a layer of endothelial cells connected by tight junction (TJ) proteins to limit paracellular transport and express influx and efflux transporters that precisely control permeation of circulating solutes including drugs (Abbott, Patabendige, Dolman, Yusof & Begley, 2010). In neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), there are multiple reports of altered BBB ultrastructure and permeability, which have been reported to affect CNS drug delivery (Pan & Nicolazzo, 2018).
Modifications to the BBB and BSCB are also reported in ALS and such modifications have the potential to impact on CNS exposure of drugs, including those that are intended to reach the brain and those for which CNS exposure leads to off-target effects. As well as riluzole and/or edaravone, individuals with ALS are prescribed 5-10 medicines intended to reach the brain for management of common ALS symptoms such as cramps, spasticity and pain (Meyer et al., 2020). In the last 12 months of life, 57.4% and 44.1% of individuals with ALS are prescribed psychoanaleptics and psycholeptics, respectively (Grande, Morin, Vetrano, Fastbom & Johnell, 2017), and any BBB/BSCB changes could impact on their CNS exposure and efficacy. In addition, individuals with ALS are often afflicted with various comorbidities including hypertension, diabetes and hypercholesterolaemia requiring medicines that do not require access into the brain (Hobson & McDermott, 2016). Any alterations to the BBB/BSCB in ALS could result in undesirable CNS accumulation of these drugs, leading to unintended neurotoxicity in people with ALS.
Therefore, characterising the status of the CNS barriers in ALS is important for both drug discovery and for optimising medicine use in individuals with ALS. A better characterisation of the status of the BBB/BSCB can guide the design of CNS barrier-targeting approaches to enhance CNS access of novel preclinical candidates for ALS. On the other hand, appreciating the status of the CNS barriers in ALS could assist in implementing strategies to minimise the CNS exposure of drugs not intending to reach the brain, so as to minimise undesirable adverse effects and ultimately improving quality of life. This review will provide a general introduction to the structure and function of CNS barriers, highlight modifications of CNS barriers in ALS and discuss how these modifications have the potential to impact on drug development and medication safety and effectiveness in ALS.
The CNS barriers