What is Excitotoxicity?
Excitotoxicity is fundamentally the pathological activity by which brain neurons get exterminated or damaged. It is a result of extreme stimulation by glutamate and other similar neurotransmitters. Excitotoxicity occurs when the glutamate receptors, for instance the AMPA and NMDA receptors, are over-stimulated by the glutamate storm.
Excitotoxins, such as kainic acid and NMDA, which bind to glutamate receptors, might lead to excitotoxicity. These permit the influx of high Ca2+ (calcium ions) levels into the cell. The entry of Ca2+ into cells stimulates several enzymes, such as proteases (calpain), endonucleases, and phospholipases. These enzymes are responsible for damaging cell structures which include DNA, cell membrane, and constituents of the cytoskeleton.
The causes of excitotoxicity could be due to the following reasons:
- Spinal cord damage
- Hearing loss due to ototoxicity or extreme noise exposure
- Traumatic brain damage
- Alzheimer’s disease
- Multiple sclerosis
- Parkinson’s disease
- ALS (Amyotrophic Lateral Sclerosis)
- Alcohol withdrawal
- Huntington’s disease
- Benzodiazepine withdrawal
Hypoglycemia is also one of the common conditions which can result in additional glutamate accumulations around the nerve cells. Blood glucose is the essential process to get rid of glutamate from the synapses at the AMPA and NMDA receptors. Patients with excitotoxicity should never descend into a hypoglycemic state. They require 5% dextrose (glucose) IV drip to avoid a hazardous glutamate concentration around AMPA and NMDA neurons. High levels of fructose can also be helpful in the absence of dextrose (glucose) IV drip.
A Japanese scientist, T. Hayashi, was the first person to observe the dangerous glutamate effects on the CNS (Central Nervous System). In 1954, he noted that by applying glutamate directly to the CNS, it could result in excitotoxicity seizures. However, his report remained overlooked for many years.
In 1957, J. P. Newhouse and D. R. Lucas again observed the dangerous effects of glutamate in a laboratory test. They injected newborn mice with monosodium glutamate, and it damaged their nerve cells in the inner retina layers.
In 1969, John Olney found that the retina cells weren’t the only ones that got damaged by the glutamate. The activity spread all over the brain, and the term “excitotoxicity” came into existence. Olney even observed the following:
- Glutamate antagonists can help to decrease neurotoxicity.
- Cell damage happened to post-synaptic nerve cells only.
- Glutamate agonists were able to stimulate glutamate receptors, although they were equally neurotoxic.
Mark Mattson conducted further studies and found that excitotoxicity could also lead to Alzheimer’s disease and other neurodegenerative disorders. He also discovered that age-related cognitive disorders involve cerebral energy shortfalls and oxidative stress.
Excitotoxicity begins with substances called endogenous excitotoxins. Your body produces excitotoxins such as glutamate in your brain, which is the primary excitatory agent in the CNS.
During normal states, glutamate accumulation can be enhanced up to 1mM in the brain. It can also be speedily reduced in milliseconds. However, when the glutamate accumulation around the synapses doesn’t get reduced, its levels increase rapidly. As a result, an activity called apoptosis begins, by which the nerve cells start to destroy themselves.
Such pathological activity can also happen due to spinal-cord damage and brain injury. Just within a few minutes post brain injury, the impaired neurons leak glutamate all over the brain. This glutamate can further activate glutamate receptors to increase the discharge of surplus glutamate.
Stroke or brain injury can also lead to ischemia. It’s a condition in which blood flow slows down to insufficient levels. Subsequently, the glutamate concentration occurs in the extracellular space which results in cell destruction. The condition is further aggravated by the deficiency of glucose and oxygen.
The pathological activities caused by ischemia condition, and the stimulation of glutamate receptors, can lead to a deep chemical coma. This condition can occur in patients with spinal cord and brain injury. It can decrease the metabolism of cerebral glucose and oxygen in the patient’s brain. Also, it can deplete its efficiency to get rid of glutamate assertively.
Enhanced glutamate levels result in the stimulation of Ca2+ (calcium ions), porous NMDA receptors on oligodendrocytes and myelin. As a result, the oligodendrocytes are vulnerable to the invasion of excess Ca2+ as well as the excitotoxicity. Among the dangerous effects of surplus Ca2+ in the Cytosol is the stimulation of apoptosis activity.
Another harmful effect of additional Ca2+ levels in the Cytosol is the creation of a pore in the mitochondrial membrane. Through this pore, the organelles soak up excess calcium ions. As a result, the mitochondria might swell and discharge reactive oxygen chemicals and other substances which can cause apoptosis. This mitochondrial pore might even cause further Ca2+ release.
The creation of ATP (Adenosine Triphosphate) might cease, and it may instead get hydrolyzed. Insufficient ATP formation due to brain injury might reduce the electrochemical gradients of some ions. Glutamate carriers need the preservation of these ion gradients to eliminate the additional accumulation of glutamate around the neurons. Inadequate ion gradients can lead to the blocking of glutamate uptake, and it’s also a hindrance to its carriers.
The glutamate carriers on astrocytes and nerve cells can reverse their glutamate movement. They can even discharge the amount of glutamate which can cause excitotoxicity. It can lead to accumulation of glutamate that can further inhibit the stimulation of glutamate receptors.
Furthermore, the influx of Ca2+ isn’t the only factor which can result in apoptosis. Recent studies suggest that the extra-synaptic NMDA receptor can be activated by either ischemic conditions or excess glutamate concentration. As a result, a protein called CREB (cAMP response element binding) gets activated. CREB protein is responsible for causing apoptosis and mitochondrial membrane pores.
Blocking Excitotoxicity or Glutamatergic storm:
There exists a neurotransmitter which can block excitotoxicity of glutamate and offer a soothing effect to your mind. It’s known as GABA (Gamma Amino Butyric Acid). Your brain naturally creates this inhibitory neurotransmitter to neutralize the excitatory effects of glutamate. GABA is the neurotransmitter which is actively involved in this task.
GABA can prominently aid in excitotoxicity reversal. The primary function of GABA is to decrease the action of the nerve cells to which it binds. When this neurotransmitter binds to a glutamate receptor, it unlocks the receptor sites. It then permits the chloride ions in your brain to enter the neurons and inhibit the neuron activities. As a result, your brain experiences a soothing feeling.
If the neurons create excess excitatory neurotransmitters, such as epinephrine or norepinephrine, it can lead to higher anxiety levels. However, if our brain is functioning normally it will create adequate GABA. In turn, it will reduce the anxiety and stress levels, which eventually will lead to a calming effect.
GABA supplements are currently available in the market, both online and over the counter. Several nootropic users are taking it for off-label purpose, to reduce depression and improve overall cognitive benefits.