Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that specifically targets and destroys motor neurons, the nerve cells responsible for controlling voluntary muscles. This loss of motor neurons in the brain and spinal cord leads to muscle weakness, atrophy, and eventual paralysis. The underlying mechanism contributing to this destruction is a phenomenon known as excitotoxicity, which involves the nervous system’s primary chemical messenger for stimulation. This messenger, called glutamate, plays a dual role in ALS, being both essential for normal function and a major pathological factor when its regulation fails.
Glutamate’s Essential Role in the Nervous System
Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, where it acts as a chemical signal to activate nerve cells. This activation is fundamental for virtually all processes, including facilitating signal transmission between motor neurons to initiate and control movement. When a signal arrives at a nerve ending, glutamate is released into the synaptic cleft, the microscopic gap between two neurons, to bind with specific receptors on the receiving cell.
This binding generates an electrical impulse, allowing the message to continue its journey to the muscle. For the system to function correctly, the signal must be brief and precise, which requires the rapid removal of glutamate from the synapse. Specialized protein structures called Excitatory Amino Acid Transporters (EAATs) handle this clearance process.
These transporter proteins, primarily EAAT2 located on surrounding support cells called astrocytes, quickly recapture glutamate from the synaptic cleft. This reuptake mechanism is highly efficient, preventing the continuous stimulation of the receiving neuron. Once inside the astrocyte, glutamate is converted into glutamine, a non-toxic molecule that is then shuttled back to the neuron to be recycled into new glutamate, completing the glutamate-glutamine cycle.
The Mechanism of Glutamate Excitotoxicity in ALS
Excitotoxicity describes the pathological process where nerve cells are damaged or killed by excessive and prolonged stimulation from excitatory neurotransmitters, with glutamate being the primary culprit. In ALS, the delicate balance of glutamate signaling is disrupted, leading to chronically elevated concentrations in the synapse. This is largely attributed to a dysfunction or loss of the EAAT2 transporter protein, which is responsible for up to 90% of glutamate clearance in the brain and spinal cord.
A significant reduction, sometimes up to 95%, in the functional EAAT2 protein is observed in the motor cortex and spinal cord of ALS patients. This failure of the astrocyte-based clearance system means glutamate lingers in the synaptic cleft, causing motor neurons to be continuously bombarded with excitatory signals. This chronic overstimulation primarily targets two types of glutamate receptors on the motor neuron: the AMPA and NMDA receptors.
The sustained activation of these receptors forces their ion channels to open for extended periods, allowing an influx of ions into the motor neuron. Excessive entry of calcium ions floods the cell’s interior. Motor neurons are uniquely vulnerable because many express a form of the AMPA receptor that is highly permeable to calcium, due to a relative lack of the GluR2 subunit.
This calcium overload triggers a cascade of events within the motor neuron. The high internal calcium levels overwhelm the cell’s internal regulatory mechanisms and severely impair mitochondrial function. This mitochondrial dysfunction leads to the generation of harmful reactive oxygen species and the activation of various enzymes, ultimately initiating the pathways that result in nerve cell breakdown and death.
Medications That Modulate Glutamate
The understanding that glutamate excitotoxicity contributes to motor neuron death led directly to the development of therapeutic strategies focused on modulating the glutamatergic system. Riluzole was the first medication approved for ALS treatment and acts as a neuroprotective agent by reducing excitotoxicity. Its mechanism involves decreasing the amount of glutamate released from the presynaptic nerve terminal.
Riluzole achieves this by blocking voltage-gated sodium channels on the neurons, which are necessary for the cell to fire an action potential and release neurotransmitters. By inhibiting these channels, Riluzole dampens the overall excitability of the motor neurons and reduces the release of glutamate into the synapse. This action indirectly lowers the glutamate concentration, thereby protecting the receiving motor neuron from toxic overstimulation.
Clinical trials have demonstrated that Riluzole offers benefit by extending the survival time for individuals with ALS. It helps delay the point at which a patient may require a tracheostomy to assist with breathing. Beyond reducing release, Riluzole inhibits certain postsynaptic glutamate receptors, providing a multi-pronged approach to neuroprotection.
Research has explored directly targeting the dysfunctional EAAT2 transporter. Compounds like ceftriaxone were investigated for their ability to increase the expression and function of EAAT2. While this approach holds theoretical promise, clinical trials for ceftriaxone did not show a modification of the disease course, highlighting the complexity of intervening in this pathological pathway.