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