Question

What are the pros and cons with using tropisetron for the treatment of Alzheimer’s disease?

Answer 1

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by formation of amyloid beta plaques and tau neurofibrillary tangles. Formation of insoluble amyloid beta plaques disrupts synaptic transmission in neurons. Tropisetron is a complete antagonist of a 5-hydroxytryptamine (5-HT)₃ receptor and a partial agonist of α7 nicotinic acetylcholine receptor (α7 nAChR). Hence, it blocks the action of serotonin at the 5-HT3 receptor.

Pros: In AD, APP is cleaved by beta secretase to form soluble APP beta protein. APP beta can then be cleaved by gamma secretase to form insoluble Amyloid beta protein. This Amyloid beta protein can bind to α7 nAChR and causes amyloid beta plaque formation and inflammation. AD leads to loss of cholinergic neurons, causing cognitive decline and AD. However, if APP is cleaved by alpha secretase enzyme, it forms soluble APP alpha, which acts as a trophic factor. Tropisetron is found to increase the formation of soluble amyloid precursor protein (APP) α by binding to APP at its Ectodomain. Thus, there is less action of beta and gamma secretase on APP, which improves the AD symptoms due to less formation of Amyloid beta plaques. Further, its antagonistic action on 5-HT3 receptor, it provides a neuroprotective and anti-inflammatory role. Its agonistic action on α7 nAChR reduces interaction between amyloid beta and α7 nAChR, thereby having an anti-inflammatory role. Thus, Tropisetron can be used to treat early stages of AD. Acetylcholine release is increased due to antagonistic effects on 5-HT3 and thereby increasing cholinergic function as well. This drug improves memory in AD patients better than other standard drugs such as memantine. This drug does not affect other acetylcholine receptors.

Cons: 5-HT3 receptor antagonist can have detrimental effects on other tissues. All tissue that exhibit 5 HT3 and α7 nAChR activities will be affected by this drug, especially heart, ECG abnormalities are observed with high doses of such antagonists. These drugs also have pro-convulsive properties. Hence, it should not be considered in AD patients having preexisting cardiovascular disease. Patients also on anti-arrhythmic or beta-adrenergic blocking agents, should not be prescribed Tropisetron. Although Tropisetron is readily absorbed by the gut, its bioavailability varies in patents based on metabolism. Patients with renal failure may exhibit higher doses of the drug, which may have increased side effects. As it is directly binds to APP, it has effects to prevent early stages of AD. However, whether it can help in late stages of AD disease would be a dilemma. Some side effects of this drug are Headache, constipation, fatigue and dizziness. As this drug is excreted in milk, it should not be given to AD patients that are breastfeeding (in early onset familial AD). High doses of Tropisetron of 30 mg/Kg/day in mice have shown benign hepatocellular neoplasia