DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

610 excitotoxic injury, regional variation in capacity for
oxidative metabolism, and the production of toxic free
radicals as by-products of cellular metabolism. New
neuroprotective agents may target the factors that convey
selective vulnerability.
SECTION II
NEUROPHARMACOLOGY
Genetics and Environment. Each of the major neurodegenerative
disorders may be familial in nature. HD is
exclusively familial; it is transmitted by autosomal
dominant inheritance, and the molecular mechanism of
the genetic defect has been defined. Nevertheless, environmental
factors importantly influence the age of onset
and rate of progression of HD symptoms. PD, AD, and
ALS are mostly sporadic without clear pattern of inheritance.
But for each there are well-recognized genetic
forms. For example, there are both dominant (α-synuclein,
LRRK2) and recessive (parkin, DJ-1, PINK1) gene
mutations that may give rise to PD (Farrer, 2006). In
AD, mutations in the genes coding for the amyloid precursor
protein (APP) and proteins known as the presenilins
(involved in APP processing) lead to inherited
forms of the disease (Selkoe and Podlisny, 2002).
Mutations in the gene coding for copper-zinc superoxide
dismutase (SOD1) account for about 2% of the
cases of adult-onset ALS (Boillée et al., 2006). Several
other less common mutations have also been described.
In addition to these monogenic forms of neurodegenerative
disease, there are also genetic risk factors that influence the probability
of disease onset and modify the phenotype. For example,
the apolipoprotein E (apo E) genotype constitutes an important risk
factor for AD. Three distinct isoforms of this protein exist.
Although all isoforms carry out their primary role in lipid metabolism
equally well, individuals who are homozygous for the apoE4
allele (“4/4”) have a much higher lifetime risk of AD than do those
homozygous for the apoE2 allele (“2/2”). The mechanism by
which the apoE4 protein increases the risk of AD is not exactly
known. ApoE4 probably has multiple effects, some of which are
mediated through altering β-amyloid (Aβ) aggregation or processing,
and some of which that are Aβ-independent (Mahley
et al., 2006).
Environmental factors including infectious agents, environmental
toxins, and acquired brain injury have been proposed in the
etiology of neurodegenerative disorders. The role of infection is best
documented in the cases of PD that developed following the epidemic
of encephalitis lethargica (Von Economo’s encephalitis) in
the early part of the 20th century. Most contemporary cases of PD
are not preceded by encephalitis, and there is no convincing evidence
for an infectious contribution to HD, AD, or ALS. Traumatic brain
injury has been suggested as a trigger for neurodegenerative disorders,
and in the case of AD there is some evidence to support this
view (Cummings et al., 1998). At least one toxin, N-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce a condition
closely resembling PD (Langston et al., 1983). More recently, evidence
has linked pesticide exposure with PD (Costello et al., 2009).
Exposure of soldiers to neurotoxic chemicals has been implicated
in ALS (as part of “Gulf War syndrome”) (Golomb, 2008). While
these examples illustrate the potential of environmental factors to
influence neurodegenerative disease, it is clear that the causes identified
so far are too few to account for more than a small minority of
the cases. Further progress in understanding the causes of neurodegenerative
disorders will require a deeper understanding of the interactions
between genetic predisposition and environmental factors,
an area that is just beginning to be explored.
Common Cellular Mechanisms of Neurodegeneration.
Despite their varied phenotypes, the neurodegenerative
disorders share some common features. For example,
misfolded and aggregated proteins are found in every
major neurodegenerative disorder: alpha-synuclein, in
PD; amyloid-β (Aβ) and tau in AD; huntingtin in HD;
and SOD and TDP-43 in ALS. The accumulation of misfolded
proteins may result from either genetic mutations
producing abnormal structure, or from impaired cellular
clearance. Age-related decline in the ability to clear misfolded
proteins may be an important predisposing factor,
and strategies to augment the clearance of misfolded
proteins are being studied as potential therapies.
The term excitotoxicity describes the neural injury
that results from the presence of excess glutamate in the
brain. Glutamate is used as a neurotransmitter by many
different neural systems and is believed to mediate most
excitatory synaptic transmission in the mammalian brain
(see Table 14–3). Although glutamate is required for
normal brain function, the presence of excessive
amounts of glutamate can lead to excitotoxic cell death
(see Figure 14–13). The destructive effects of glutamate
are mediated by glutamate receptors, particularly those
of the N-methyl-D-aspartate (NMDA) type. Excitotoxic
injury contributes to the neuronal death that occurs in
acute processes such as stroke and head trauma (Choi
and Rothman, 1990). The role of excitotoxicity is less
certain in the chronic neurodegenerative disorders; nevertheless,
regional and cellular differences in susceptibility
to excitotoxic injury, conveyed, e.g., by differences in
types of glutamate receptors, may contribute to selective
vulnerability. This has led to the development of
glutamate antagonists as neuroprotective therapies, with
two such agents (memantine and riluzole, described
later) currently in clinical use.
Aging is associated with a progressive impairment in the
capacity of neurons for oxidative metabolism, perhaps in part
because of a progressive accumulation of mutations in the mitochondrial
genome. A consequence of impaired oxidative capacities is the
production of reactive compounds such as hydrogen peroxide and
oxygen radicals. Unchecked, these reactive species can lead to DNA
damage, peroxidation of membrane lipids, and neuronal death. This
has led to pursuit of drugs that can enhance cellular metabolism