Neuroprotective Drugs: Future Developments in Treating Vascular Dementia

Vascular dementia accounts for 10% to 20% of dementia occurring in people over 65 years of age. Its prevalence in this age group is 1% to 4%, while above the age of 80 years it affects 14% to 16% of people.

Vascular Dementia

Image Credit: Atthapon Raksthaput/Shutterstock.com

This is a large segment of society, yet there is no currently approved treatment for it.

What causes vascular dementia?

Vascular disease, affecting the blood supply to the neurons of the brain, causing their death, is the fundamental cause of vascular dementia. Hemorrhage and hypoperfusion cause nerve cells to degenerate by cutting off oxygen and glucose supplies.

The result is that the neuron membrane depolarizes. This, in turn, triggers excessive glutamate release, with over-activation of the N-methyl-D-aspartate (NMDA) receptor/channel complex (NMDAR).

The subsequent inflow of calcium ions into the neurons activates intracellular calcium-dependent enzymes. This indicates glutamate toxicity mediated by ionotropic glutamate receptors.

Initial attempts to treat such damage were by targeting the glutamate receptor, especially those of the NMDAR subtype. Unfortunately, successful animal trials could not be replicated in humans due to psychosis, nausea, vomiting, poor memory, and sometimes the death of the cell.

Only four therapies tested in almost 300 clinical trials were at all successful, most of them being thrombolytic drugs. Neuroprotective drug trials have never reported success, for many and various reasons.

What drugs were tried?

Researchers have looked into various categories of drugs, such as vasodilators, antithrombotic, serotoninergic, cholinergic, antiglutamatergic, and rheological drugs.

Some of the neuroprotective drugs that were tested for their effect on vascular dementia include:

  • Memantine
  • Galamantine
  • Donepezil
  • Rivastigmine
  • Hydergine
  • Nicergoline
  • Nimodipine

Memantine

Memantine is similar to the antiviral anti-Parkinson drug amantadine, which stimulates the release of dopamine from dopamine-releasing neurons.

It shows weak antagonism at the NMDAR. NMDAR antagonists cause hallucinations and poor cognition, but memantine unexpectedly produced a cognitive improvement, perhaps indicating that it acts by some other mechanism.

It could be combined with an acetylcholine esterase inhibitor for greater benefit.

Galantamine

Galantamine is a cholinesterase inhibitor and a modulator of n-cholino receptors, with no significant known benefit in Alzheimer’s disease. Study results do not encourage the use of this compound in vascular dementia.

Donepezil

Donepezil is also an acetylcholinesterase inhibitor and improves cognition, global assessment and activities of daily living. Some researchers think it is the most promising drug for the treatment of vascular dementia in its class.

Rivastigmine

Rivastigmine is an inhibitor of two cholinesterases, but the evidence is too weak to support its use in vascular dementia.

Hydergine

Hydergine is a mixture of four compounds derived from ergotoxine or ergoloid mesylates with the Food and Drug Administration’s (FDA) approval for treating “idiopathic decline in mental capacity”.

It has a dose-dependent benefit for global measures, but more research is needed to find out if it is helpful in vascular dementia.

Nicergoline

Nicergoline is also an ergot derivative in use for disorders of mood, cognition and behavior in older people for over 3 decades. It acts via multiple neurotransmitters and several intracellular signaling pathways. Evidence is mixed, favoring improvement in vascular dementia. However, modern diagnostic criteria must be used to validate these results.

Nimodipine

Nimodipine is a calcium-channel blocker that might reduce the opening of voltage-dependent calcium channels and thus prevent the aggravation of the calcium-dependent excitotoxic effect due to the NMDAR-mediated calcium ion influx.

However, though nimodipine improves regional blood flow in the brain with beneficial effects on the hippocampus, reduced inflammatory markers, and better memory acquisition in animal ischemia models, clinical effects are negligible in humans.

Anti-hypertensive drugs

Anti-hypertensive drugs including nicardipine, other calcium channel blockers, and angiotensin II receptor blockers (ARBs), have been given to patients with hypertension but without cognitive impairment, in three randomized placebo-controlled trials to see if blood pressure control could reduce the odds of vascular dementia.

However, this was not observed to happen. It may be that such treatment is too late to prevent damage.

Angiotensin-converting enzyme inhibitors like captopril and perindopril may reduce oxidative stress and improve cognitive function, but the evidence is lacking.

CDP choline

CDP choline is used to treat cognitive disorders arising as a result of vascular disease, because, under ischemic conditions, it inhibits the breakdown of the membrane and the release of pro-inflammatory arachidonic acid. Its proven benefits are modest, however, and more research is needed in this area.

Folic acid

Folic acid is a vitamin crucial in the prevention of neural tube abnormalities in the developing embryo. Its deficiency pushes up the levels of homocysteine, a nerve toxin that causes depression and dementia. Short trials of folic acid found no benefit on cognitive function.

Propentofylline

Propentofylline is a drug that blocks adenosine uptake, inhibiting the phosphodiesterase enzyme in the brain neurons. It suppresses microglial activation and inhibits the production of free radicals. It was tested in this condition because of its anti-inflammatory action, but the evidence is weak.

Posatirelin

Posatirelin is a tripeptide with neurotrophic, cholinergic and catecholaminergic activity. It is a synthetic analog of thyrotropin-releasing hormone, but it has greater effects on the central nervous system than on the hormonal axis. Despite some evidence of benefit, it is not in clinical use.

Conclusion

The inconclusive findings of most of these studies show that neuroprotective drug discovery needs to be directed by the analysis of the mechanisms that make the cell more vulnerable to injuries, such as inhibition of endocytosis, activation of the inflammatory response, of cell apoptosis and the transcription of certain genes.

A multi-target approach will be necessary to evolve a more effective treatment of vascular dementia via all these mechanisms.

A ray of hope comes from the modest improvement reported with the use of acetylcholine esterase inhibitors (ACE inhibitors), which could be used with antithrombotics and perhaps with memantine.

Sources

Further Reading

Last Updated: Jan 28, 2021

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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