Web Box 8.2 Clinical Applications: Examples of Excitotoxic Brain Damage in Medicine

One of the clearest examples of excitotoxic brain damage in humans is the damage produced by ingesting large amounts of a toxic excitatory amino acid called domoic acid. This toxin is made by several species of marine algae, especially diatoms of the genera Pseudo-nitzschia and Nitzschia. Domoic acid from these algae is taken up and concentrated by certain shellfish, crabs, and fish, from which it is passed on to other marine wildlife as well as humans who eat the tainted food (Saeed et al., 2017; Figure 1). Many dolphins, sea lions, and seabirds have become ill and died from ingesting this substance. In fact, Alfred Hitchcock’s film The Birds is believed to have been based on a 1961 incident in Santa Cruz County, California, in which domoic acid–poisoned seabirds began to crash into pedestrians, automobiles, and buildings (Bargu et al., 2012). In reality, the birds were not attacking the town, but rather had become weak and disoriented because of the effects of the toxin.

Domoic acid poisoning in humans first came to the attention of health officials in 1987, when more than 100 people in Prince Edward Island, Canada, were afflicted after consuming blue mussels contaminated with domoic acid. The victims developed various neurological symptoms such as headache, dizziness, muscle weakness, mental confusion, and, in some cases, permanent loss of short-term memory. Three people died. Since that time, unsafe levels of domoic acid in seafood have periodically been found off the west coast of the United States and Canada, and in numerous western Pacific Ocean countries, including Japan, Philippines, Malaysia, Vietnam, and Australia (Bates et al., 2018; Smith et al., 2018).

 Even though local and national governments regulate seafood consumption when domoic acid levels are high, groups that routinely eat large amounts of shellfish experience long-term exposure to lower amounts of this toxin. One such group consists of Native Americans living along the Washington State coast who are regularly exposed to domoic acid through their consumption of razor clams containing varying amounts of the toxin. Recent studies have documented memory deficits in this population that are correlated in severity with their domoic acid exposure (Grattan et al., 2018; Stuchal et al., 2020). Consequently, programs have been developed involving government regulatory agencies, tribal leaders, and local physicians to educate the population to recognize the danger and to assist in reducing toxin exposure.

Excitotoxic brain damage also occurs in people who experience brain ischemia, which is an interruption of blood flow to the brain (Amantea and Bagetta, 2017; Mayor and Tymianski, 2018). Ischemia can result from either a stroke (focal ischemia, usually caused by an embolism that impedes blood flow to a specific region of the brain) or, less commonly, a heart attack (global ischemia, where blood flow to the entire brain is interrupted). Depending on the affected area, stroke may cause severe impairments in motor function, sensory mechanisms, language, or memory. This neurological disorder is also the second most frequent cause of mortality beyond the age of 60 years (Chamorro et al., 2016). When a stroke occurs, brain tissue that is completely or nearly completely deprived of oxygen rapidly dies. This is the core area of the stroke, and no known treatment can prevent this brain damage from occurring. In contrast, there is a larger volume of tissue surrounding the ischemic core, called the penumbra, that experiences only partial oxygen deprivation (Figure 2). Since cells within the penumbra do not die right away, there is hope that this brain tissue can be salvaged, thereby limiting the consequences of the stroke to the patient. The problem with attempting to rescue the cells within the penumbra is that the partial oxygen deprivation leads to massive neuronal depolarization because the ion pumps that maintain the resting potential require a constant generation of ATP, which, in turn, requires oxygen. This membrane depolarization causes a massive release of glutamate in the affected area, thereby leading to prolonged activation of NMDA receptors, including the GluN2B-containing receptors that trigger the neuronal excitotoxic cell death pathway (Patel and McMullen, 2018; Ge et al., 2020) (Figure 3). In addition, oligodendrocytes express AMPA, kainate, and NMDA receptors containing GluN2C and GluN2D subunits, and glutamate activation of these receptors contributes to stroke-related oligodendrocyte death and myelin (white matter) damage (Fern and Matute, 2019; Ge et al., 2020).

Using animal models of focal ischemia, researchers have tested the effects of blocking NMDA receptor activation with drugs that target glutamate binding, binding at the co-agonist (glycine/d-serine) site, or the PCP binding site within the receptor channel. These approaches have all proved successful in reducing the amount of ischemic cell death. Unfortunately, a large number of human clinical trials with the same drugs have thus far been largely disappointing (Chamorro et al., 2016). Compounds that appeared promising in preclinical studies failed to show therapeutic benefit in patients and sometimes led to severe side effects. Indeed, uncompetitive NMDA receptor antagonists that bind to the PCP site within the receptor channel can produce psychotic-like symptoms in people (see Chapter 15). Some researchers have theorized that even when a drug is well tolerated by patients, the treatment may have failed because of the time lag between the stroke and beginning the treatment (i.e., it may be too late to prevent excitotoxicity by blocking the NMDA receptors).

The failure of previous clinical trials involving generalized NMDA receptor blockade has led to new therapeutic approaches, some involving this same receptor but others invoking different mechanisms of action. For example, because of the different cellular effects of extrasynaptic NMDA receptors (pro-death) compared to synaptic NMDA receptors (pro-survival), one possible strategy is to simultaneously block the former while activating the latter using subtype-selective drugs (Ge et al., 2020). A second strategy is aimed at inhibiting the cell death pathways triggered by NMDA receptor activation instead of targeting the receptors themselves (Wu and Tymianski, 2018). Another interesting idea is to enhance clearance of the excessive glutamate by increasing expression or activity of glutamate transporters, especially the key astrocyte transporter EAAT2 (Fontana, 2015; Wang and Harvey, 2016). Given the aging population in the United States and other developed countries, finding more effective therapies for stroke patients is of prime importance in the area of drug development.

Excitotoxic cell death in ischemic stroke is an acute process provoked by rapid increases in extracellular glutamate levels. Acute domoic acid poisoning following high-dose exposure similarly occurs over a relatively short time period. On the other hand, there is also evidence for a chronic, slower-acting excitotoxic process that may be present in other CNS disorders (Lewerenz and Maher, 2015). For many years, excitotoxicity has been hypothesized to be one of the factors involved in amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or, colloquially, Lou Gehrig’s disease. ALS is a fatal neurological disorder involving a slow but progressive degeneration of motor neurons both in the spinal cord and in the neocortex (Geevasinga et al., 2016; Le Gall, 2020; see Chapter 20 for more information on this disorder, including currently available drug treatments). Three different hypotheses have been advanced to account for the degeneration of motor neurons in these two different locations: (1) dying-forward hypothesis, in which motor neuron degeneration begins in the cortex and then spreads to the spinal cord; (2) dying-back hypothesis, in which the spinal cord motor neurons degenerate first; and (3) independent degeneration hypothesis, in which the two kinds of motor neurons are affected separately from each other (Geevasinga et al., 2016; Figure 4). Some cases of ALS can be traced to genetic mutations; however, the majority have no known cause. Evidence for glutamate-mediated excitotoxicity in ALS is based largely on evidence for glutamate receptor upregulation in motor neurons obtained from ALS patients (Selvaraj et al., 2018; Shi et al., 2019) and findings of cortical hyperexcitability in patients tested using transcranial magnetic stimulation (TMS; van den Bos et al., 2019). Importantly, none of this evidence is proof of glutamate excitotoxicity in ALS, and even if such a process does occur, it is almost certainly only one of several factors contributing to this disorder.

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