The level of cytosolic Mg 2+ in the brain is estimated to be about half that in skeletal muscle, and its reduced concentration is associated with neurological diseases facilitated by reduced ATP production and altered Na + /K + ATPase activity. The BBB plays an important role in separating the extracellular fluid (ECF) from the blood circulation.

The concentration of Mg 2+ in the ECF is higher than that in the CSF and plasma. This indicates that Mg 2+ is actively transported into the brain. The concentration of Mg 2+ in the CSF is interrelated with various brain functions and is altered in various neurological disorders. Mg 2+ concentration in the brain is related to neuronal excitability, caused by various neurotransmitters, glutamate, which acts on the D -aspartate receptor …NMDA and the propionic acid receptor …AMPA, kainite and metabotropic receptors present in postsynaptic membranes. Normally the NMDA receptor is blocked by Mg 2+, so that glutamate acts only on the AMPA receptor. AMPA activation facilitates ionic movement across neuronal membranes and thus activates NMDA receptors.

Deficiency of extracellular Mg 2+ results in hyperexcitability of neurons due to over-activation of NMDA. In addition to the NMDA receptor, Mg 2+ can modulate the inhibitory GABA A receptor, the activation of which causes an influx of chloride ions, causing neuronal hyperpolarization and inhibition. Mg 2+ is considered as an agonist of the GABA A receptor, which acts on benzodiazepines [like receptors] and exhibits anxiolytic effects. This effect is antagonized by flumazenil [GABA receptor antagonist], confirming the agonistic property of Mg 2+ at this receptor.

Low level of Mg 2+ in the CNS may reduce GABA A receptor activity, resulting in higher membrane potential contributing to excitotoxicity In addition, if extracellular Mg 2+ is found to be less, there is increased calcium influx, which increases glutamate release and thereby causes excitotoxicity. Another vital activity of Mg 2+ in the brain is its inhibitory effect on oxidative stress ,from increased ROS production and cell death. Mg 2+ deficiency promotes the release of inflammatory mediators [IL-6 and TNF-α] via activation of substance P. In addition, Mg 2+ activates nitric oxide synthase, increases NO production. involved in vasodilation, channel regulation and neurotransmitter release.

Magnesium and neurological diseases

Mg 2+ deficiency has been reported in various diseases such as migraine, stroke, neurodegenerative diseases, depression, epilepsy, etc.

It is reported that BBB breakdown, edema, excitotoxicity and ROS production associated with neurological diseases can be corrected using Mg 2+ . Excessive calcium influx into the brain can cause various complications in the brain, including excitotoxicity, BBB disruption, inflammation, and oxidative stress. Magnesium inhibits calcium influx, substance P production, inflammation and oxidative stress.


Migraine, a recurrent throbbing headache, is associated with activation of the NMDA receptor, the release of Peptide-CGRP (causes vasodilation) and 5-HT with consequent activation of platelets.

The level of Mg 2+ was found to be lower in the serum and CSF of migraine patients. Mg 2+ exhibited anti-migraine activity by inhibiting NMDA receptor activation, CGRP release and platelet hyperaggregation. Mg 2+ acts in migraine by various mechanisms such as the regulation of the action of neurotransmitters (serotonin, NO and glutamate), the increase of ATP production, the reduction of platelet aggregation and the anti-inflammatory effect. Intravenous magnesium can reduce acute migraine attacks. meanwhile, oral administration of magnesium reduces attack intensity and frequency.Research paper reports revealed that magnesium sulfate supplement was found to be effective in migraine with aura, but not effective in common attacks. While magnesium citrate has been found to be effective in migraine without aura.

CNS injury

Traumatic CNS injury can result in a 40–60% decrease in the intracellular Mg 2+ level with a 10–15% decrease in the total Mg 2+ level. which can affect glutamate and calcium entry into the presynaptic neuron. This results in neurodegeneration and cell death secondary to brain damage. Secondary injuries include diffuse axonal damage, edema (both angiogenic and cytotoxic), extrasynaptic NMDA receptor-mediated toxicity , neurogenic inflammation, oxidative stress, mitochondrial dysfunction and inflammation. Various studies have reported that Mg 2+ deficiency accelerates the release of substance P and proinflammatory mediators. There are several mechanisms that mediate the neuroprotective effect of Mg 2+ in CNS injury.

1] First and foremost among these is the blockade of the NMDA receptor by Mg 2+ , which is responsible for excitotoxicity.

2] The second is to provide protection from the oxidant, by reducing the generation of ROS and lipid peroxidation.

3]The third mechanism is by maintaining the integrity of the mitochondrial membrane through reduced lactic acid production and there by correcting mitochondrial dysfunction.

Parkinson’s disease

The disease is characterized by the loss of dopaminergic neurons in the basal ganglia, and excitotoxicity is considered to be one of its main causes. Possible mechanisms are mitochondrial damage associated with increased ROS production and endoplasmic stress. Mitochondrial dysfunction resulted in the accumulation of α-synuclein, which with iron causes oxidative stress, resulting in the combination of the Parkin and DJ1 genes, which prevent protein destruction. Normally, misfolded protein aggregates and damaged organelles are degraded by autophagy, by lysosomes, and impairment of this pathway leads to synuclein accumulation. Mg 2+ transporter SLC41A2 plays a role in disease progression Mg 2+ is effective in the treatment of Parkinson’s disease by [1] inhibiting the aggregation of α-synuclein with iron and other metals and [2] regulating the mTOR pathway which is involved in deactivating autophagy, responsible for synuclein accumulation. Mg 2+, by regulating the mTOR pathway, reduces synuclein formation and protects dopaminergic neurons. In addition, the prevention of neuroinflammation by Mg 2+ also contributes an additional protective effect in the treatment of PD.

Alzheimer’s disease

AD, with cholinergic transmitter loss in the CNS, is characterized by the accumulation of extracellular senile plaques and intracellular tangles within brain cells, along with inflammation and atrophy. A low level of Mg 2+ was found in the CSF and hair of AD patients, with no significant change in serum Mg 2+ level, compared to normal subjects. Extracellular Mg 2+ has been reported to control BBB permeability of amyloid β plaque in ECF and enhance its clearance. Mg 2+ exhibits anti-inflammatory property by reducing the expression of TNF-α and the production of pro-inflammatory mediators, which also contribute to the beneficial effect in the AD condition. Low extracellular Mg 2+ initiates the breakdown of amyloid precursor protein (APP) by secretases [Neurotoxic products], while high extracellular Mg 2+ switches the pathway to form a soluble form of APP, which is neurotrophic. Furthermore, Mg 2+ inhibits the enzyme glycogen synthase kinase-3β (GSK-3β) (involved in cell apoptosis), reduces neuronal cell death, improves cognitive function and synaptic plasticity in an AD model.


The anticonvulsant effect of Mg 2+ is caused by antagonism of the NMDA receptor, the increase in the production of vasodilator prostaglandin and the stabilization of the neuronal membrane. Mg 2+ is a potent modulator of seizure activity by inhibiting calcium influx through the NMDA receptor. In addition, low Mg 2+ reduces the surface charge of the neuronal membrane and results in hyperexcitability Mg 2+ acts as cofactor in GABA synthesis, which is also responsible for its anticonvulsant action. Higher dietary Mg 2+ intake is associated with a lower incidence of epilepsy and is thought to be caused by reduced production of C-reactive protein. Na + /K + ATPase activity also changes with a decrease in Mg 2+ concentration, which increases seizure susceptibility. Mg 2+ has a beneficial role in correcting the reduced levels of synaptically released GABA associated with drug-resistant epilepsy (DRE). Thus, Mg 2+ supplementation reduces the number of seizure days per month in patients with DRE. In epileptic patients, low serum Mg 2+ may be associated with fatal cardiac events and cause sudden unexpected death. Magnesium sulfate has also been found to be effective in refractory status epilepticus due to febrile illness.

SOURCE: University hospital Basel, Cell 2024.