What Are the Uses of Neuroprotective Agents in Stroke?

Neuroprotective agents theoretically can reduce secondary brain damage from a stroke. No drug for this purpose has been FDA-approved, but many are under study.

A stroke is an interruption in blood supply to a part of the brain causing brain tissue damage. Stroke is a medical emergency and one of the leading causes of death and adult disability.

The three main types of strokes are:

• Hemorrhagic stroke: Blood vessel rupture in the brain that leads to bleeding and tissue damage.
• Ischemic stroke: Blockage of a blood vessel in the brain which interrupts blood supply to a part of the brain leading to cell death from lack of oxygen and nutrients.
• Transient ischemic attack: Brief blockage of blood supply to a part of the brain. Known as mini-strokes, transient ischemic attacks usually last just a few minutes, but are a warning sign for future ischemic strokes.

Currently, the only approved medical therapy for an ischemic stroke is with a medication known as tissue plasminogen activator. Tissue plasminogen activator is an enzyme that helps dissolve the blood clot blocking the blood vessel. The medication is usually administered intravenously within the first three hours after symptoms of an ischemic stroke.

Neuroprotective agents are medications that are being studied for use in ischemic stroke patients, to minimize damage and prevent further injury to partially damaged nerve cells (neurons). The target of neuroprotective agents is to improve functional recovery in ischemic stroke patients by reducing the impact of the stroke.

The neurons in the rim (penumbra) of the core ischemic region are less likely to suffer irreversible damage, and can revive with resumption of blood flow. Animal studies indicate that the penumbral neurons remain viable for about four hours after a stroke.

The research on the use of neuroprotective agents is with the aim of protecting the penumbral neurons from irreversible damage, and promoting neuronal healing. Neuroprotective agents may be useful in protecting penumbral neurons from two types of injury that can occur after a stroke:

Early ischemic injury

The loss of blood supply causes cellular injury by inducing excessive activation of certain cell mechanisms such as:

• Activation of excitatory amino acid receptors and release of neurotransmitters (chemicals that transmit signals between neurons)
• Accumulation of calcium in the cells
• Release of toxic products

Neuroprotective agents used for limiting early ischemic injury work by preventing the release of excitatory neurotransmitters, which may reduce the ischemic effects on the neurons in the penumbral region.

Reperfusion injury

Resumption of blood flow after dissolution of the blood clot brings oxygen to the ischemic tissue, but it can also cause injury. Reperfusion injury may result because of the following reasons

• White cells in the blood can block small blood vessels which are affected by partial ischemia, and cause further ischemia.
• Leucocytes also release toxic products that can lead to formation of free radicals and inflammatory proteins (cytokines).

Neuroprotective agents used to prevent reperfusion injury work in the following ways

• Prevent the white cells from adhering to the blood vessel walls
• Limit formation of free radicals and cytokines
• Promote repair of the affected neurons

Although many neuroprotective agents are being studied for preventing neuronal injury from a stroke, there has been no positive results for efficacy in reducing stroke-related injury. As of 2020, the FDA had not approved any neuroprotective agent for use in stroke patients.

Following sections contain some of the neuroprotective agents that have been studied for efficacy in reducing neuronal injury from stroke.

N-methyl-D-aspartate receptor antagonists

N-methyl-D-aspartate (NMDA) receptor antagonists are the most commonly studied neuroprotective agents for use in strokes. NMDA receptor antagonists are medications that bind to NMDA receptors on the neurons and block neurotransmitters from activating them. An agonist drug activates a cell’s receptors while an antagonist blocks their activity.

Cell receptors are protein molecules present in the cell membrane, which bind to specific neurotransmitters and activate the cells appropriately. NMDA receptors are a type of neuronal receptors that bind to certain excitatory neurotransmitters such as glutamate, and activate the neurons. Preventing the penumbral neuron activation may limit ischemic injury.

Following are some of the NMDA receptor antagonist drugs investigated for efficacy in minimizing early ischemic injury

• Dextrorphan: Clinical trials have not shown significant neuroprotective effects. Side effects that limit its use include:
• Hallucination
• Agitation
• Hypotension
• Sulfotel: Clinical trials indicated higher mortality in patients and trials were stopped prematurely.
• GV150526: No improvement was noted in three months and no further trials are planned.
• Magnesium: Studies found that it was safe and feasible to initiate magnesium sulfate treatment by paramedics to reduce the time to treatment. There was no improvement in disability outcomes over the three months of the study, however.

Non-NMDA receptor antagonists

Modulating the activity of certain non-NMDA receptors may also prevent the release of excitatory neurotransmitters. Following are some of the drugs that have been used in clinical trials in stroke patients.

• Nalmefene (Cervene): A narcotic receptor antagonist with minimal side effects, but no clinical benefit was found. No further trials are planned.
• Lubeluzole: Exact mechanism of action is not clear but may block sodium channels and prevent cellular activity. Clinical trials did not confirm efficacy that was observed in animal models, and research was abandoned.
• Clomethiazole: An agonist of gamma-aminobutyric acid (GABA), which is an inhibitory neurotransmitter. Clinical trials did not show significant improvement in functional outcomes at three months.

Other drugs

Some of the other drugs that were investigated in clinical trials before being discontinued for lack of efficacy were

• Calcium channel blockers: To prevent intracellular calcium build-up
• Potassium channel modulators: To decrease intracellular calcium
• Repinotan: Agonist for serotonin, an inhibitory neurotransmitter
• Tirilazad: Free radical scavenger to clear free radicals
• NXY-059: Free radical trapping agent

Other products

Other neuroprotective products for early ischemic injury which are being investigated include

• Albumin: A protein made by the liver, which has antioxidant properties and ability to increase blood flow to the penumbral region. The trial was stopped early because results were not promising.
• Hypothermia and caffeinol: A combination of caffeine and low-dose ethanol, along with mild hypothermia produced neuroprotective effects in animal models and is currently being evaluated.

Following are some of the neuroprotective agents being evaluated for use in reperfusion injury prevention:

Enlimomab

Enlimomab is a monoclonal antibody produced in mice (murine), which can prevent the white cells from adhering to blood vessels and causing a block. Clinical trials with enlimomab produced worse outcomes than placebo in stroke patients. The adverse effects were possibly due to immune response to the murine antibody.

Hu23F2G

A human antileukocytic antibody, Hu23F2G did not produce an immune response in clinical trials, but there was no clinical benefit. No further studies are planned.

Tetracycline antibiotics

A clinical trial with minocycline, a tetracycline antibiotic, showed improvement in stroke outcome by reducing leukocyte infiltration. Minocycline also appears to reduce risks of cerebral hemorrhage resulting from clot dissolution.

Antiplatelet antibodies

Abciximab (ReoPro) is an antiplatelet antibody that inhibits platelet aggregation, preventing additional ischemia and clot formation. Clinical trial was discontinued because of high risks of cerebral hemorrhage.

Citicoline

Citicoline is a substance that helps in cell membrane’s biosynthesis and may reduce ischemic injury by stabilizing the neuronal membrane. Clinical trials have shown that citicoline is safe for stroke patients and prolonged use after the stroke may be effective in improving functional recovery.

Several studies have been conducted to investigate substances that can enhance neuronal healing after an ischemic stroke.

Fiblast

Fiblast is a fibroblastic growth factor, a type of protein that helps in wound healing and cell multiplication. Trials have been discontinued due to poor risk-to-benefit ratio.

Autologous mesenchymal stem cells

Autologous mesenchymal stem cells are produced in the bone marrow and important for tissue repair. Studies are in progress for feasibility and safety of using these stem cells in stroke patients.

GSK249320

After a stroke, the levels of a protein known as myelin-associated-glycoprotein (MAG) spontaneously increases in the penumbral region.

GSK249320 is a monoclonal antibody that blocks MAG. Animal studies have shown it might be safely used in stroke patients to promote neuronal healing.