Uses of Neuroprotective Agents in Stroke

Neuroprotective agents can reduce brain damage caused by stroke. Although no FDA-approved drugs exist for this purpose, many are currently being studied.

Stroke, an interruption of blood supply to the brain, results in brain tissue damage. It is a life-threatening medical emergency and a leading cause of death and adult disability.

The three main types of strokes are:

• Hemorrhagic stroke: Rupture of a blood vessel in the brain, causing bleeding and tissue damage.
• Ischemic stroke: Blockage of a brain blood vessel, cutting off blood supply and nutrients to the affected area, resulting in cell death from lack of oxygen.
• Transient ischemic attack: Temporary blockage of blood supply to the brain, known as mini-strokes, acting as a warning for future ischemic strokes.

Mode of Action for Ischemic Stroke

Currently, the only FDA-approved medical therapy for an ischemic stroke is tissue plasminogen activator. This enzyme dissolves blood clots blocking blood vessels and is usually given intravenously within three hours after stroke symptoms occur.

What are Neuroprotective Agents?

Neuroprotective agents are medications being studied for use in ischemic stroke patients to minimize damage and promote functional recovery in partially damaged nerve cells. These agents aim to improve the outcome of stroke by reducing its impact.

Neurons in the penumbra, the outer edge of the ischemic region, can recover if blood flow is restored within approximately four hours after stroke onset, according to animal studies.

Uses of Neuroprotective Agents in Stroke

Research on neuroprotective agents aims to protect penumbral neurons, minimizing irreversible damage and promoting neuronal healing after a stroke. These agents can be useful in combating two types of stroke-related injuries:

Early ischemic injury

Loss of blood supply triggers cellular injury by overactivating specific cell mechanisms, such as:

• Activation of excitatory amino acid receptors and neurotransmitter release
• Accumulation of calcium in cells
• Release of toxic products

Neuroprotective agents prevent the release of excitatory neurotransmitters, reducing ischemic effects on penumbral neurons.

Reperfusion injury

While resumption of blood flow after clot dissolving restores oxygen to ischemic tissue, it can also cause further injury. Reperfusion injury can occur due to:

• Blockage of small blood vessels by white blood cells, exacerbating partial ischemia
• Release of toxic products by white blood cells, leading to the formation of free radicals and inflammatory proteins

Neuroprotective agents prevent the adherence of white blood cells to blood vessel walls, limit the formation of free radicals and inflammatory proteins, and promote neuronal repair.

Neuroprotective Agents for Stroke

Although many neuroprotective agents are being studied, none have shown efficacy in reducing stroke-related injury, and the FDA has not approved any for stroke patients as of 2020.

The following sections highlight some neuroprotective agents studied for efficacy in reducing neuronal injury from stroke.

Prevention of Early Ischemic Injury

N-Methyl-D-Aspartate Receptor Antagonists

N-Methyl-D-Aspartate (NMDA) receptor antagonists are commonly studied neuroprotective agents for stroke. These medications bind to NMDA receptors on neurons, blocking neurotransmitters from activating them. NMDA receptors are responsible for binding certain excitatory neurotransmitters like glutamate and activating neurons. Preventing activation of penumbral neurons can potentially limit ischemic injury.

The following are some NMDA receptor antagonist drugs investigated for efficacy in reducing early ischemic injury:

• Dextrorphan: Clinical trials have not shown significant neuroprotective effects, and its use is limited by side effects like hallucination, agitation, and hypotension.
• Sulfotel: Clinical trials indicated higher mortality rates, leading to the premature termination of trials.
• GV150526: No improvement was observed after three months, and no further trials are planned.
• Magnesium: Studies found it safe and feasible to initiate magnesium sulfate treatment to reduce treatment time. However, there was no improvement in disability outcomes after three months.

Non-NMDA Receptor Antagonists

Modulating the activity of specific non-NMDA receptors can also prevent the release of excitatory neurotransmitters. The following drugs have been used in clinical trials for stroke patients:

• Nalmefene (Cervene): A narcotic receptor antagonist with minimal side effects, but no clinical benefit was found. No further trials are planned.
• Lubeluzole: Its exact mechanism of action is unclear but might involve blocking sodium channels to prevent cellular activity. Clinical trials did not confirm observed efficacy in animal models, leading to discontinued research.
• Clomethiazole: An agonist of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. Clinical trials did not show significant improvement in functional outcomes at three months.

Other Drugs

Other drugs investigated in clinical trials that were discontinued due to lack of efficacy include:

• Calcium channel blockers: To prevent intracellular calcium buildup
• Potassium channel modulators: To decrease intracellular calcium
• Repinotan: Serotonin agonist, an inhibitory neurotransmitter
• Tirilazad: Free radical scavenger to clear free radicals
• NXY-059: Free radical trapping agent

Other Products

Other neuroprotective products being investigated for early ischemic injury prevention include:

• Albumin: A protein with antioxidant properties produced by the liver, which can increase blood flow to the penumbral region. The trial was stopped early due to unpromising results.
• Hypothermia and caffeinol: A combination of caffeine and low-dose ethanol, along with mild hypothermia, showed neuroprotective effects in animal models and is currently under evaluation.

Prevention of Reperfusion Injury

The following neuroprotective agents are being evaluated for preventing reperfusion injury:

Enlimomab

Enlimomab is a monoclonal antibody produced in mice that prevents white blood cells from adhering to blood vessels and causing blockages. However, clinical trials with enlimomab resulted in worse outcomes than a placebo, possibly due to an immune response to the mouse antibody.

Hu23F2G

Hu23F2G, a human antileukocytic antibody, did not produce an immune response in clinical trials but did not show any clinical benefits. No further studies are planned.

Tetracycline Antibiotics

Minocycline, a tetracycline antibiotic, improved stroke outcomes by reducing leukocyte infiltration. Minocycline also appears to reduce the risk 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. The clinical trial was discontinued due to a high risk of cerebral hemorrhage.

Citicoline

Citicoline promotes cell membrane 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 a stroke may aid in functional recovery.

Neuronal Healing

Several studies focus on substances that can enhance neuronal healing after an ischemic stroke.

Fiblast

Fiblast, a fibroblastic growth factor that aids in wound healing and cell multiplication, did not show a favorable risk-to-benefit ratio, leading to discontinued trials.

Autologous Mesenchymal Stem Cells

Autologous mesenchymal stem cells sourced from the bone marrow play a vital role in tissue repair. Studies are ongoing to assess the feasibility and safety of using these stem cells in stroke patients.

GSK249320

In the penumbral region, levels of myelin-associated-glycoprotein (MAG), a specific protein, spontaneously increase after a stroke.

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

Summary

Neuroprotective agents are being studied for use in some stroke patients to minimize damage and prevent further injury to partially damaged neurons. Their goal is to improve functional recovery by reducing the impact of stroke.