Alzheimer's Disease is the most common cause of dementia accounting for 60-80% of dementia cases. Alzheimer's disease is a progressive disease that reduces the longevity and quality of life for many by severely impairing cognitive ability and day to day functions. There is no definitive treatment for Alzheimer's disease, but emerging evidence is beginning to shed light upon the underlying causes of Alzheimer's.
Alzheimer’s disease (AD) is caused by deposition of Tau protein (TauP) and senile plaques comprising amyloid β (Aβ) peptides. Plaque accumulation induces oxidative stress leading to release of oxidized mediators that activate the thromboxane A2 receptor (TPr). TPr is expressed on platelets and is stimulated with thromboxane A2 (TxA2) to induce platelet activation. Platelets are the primary source (~90%) of Aβ peptide in human blood, while the Aβ peptide variants secreted by platelets are similar to those found in the senile plaques of Alzheimer's Disease patients (Kucheryavykh et al, Int J Mol Sci, 2018). Therefore, platelet activation through TPr likely contributes to Aβ accumulation in Alzheimer's Disease. TPr antagonists have been shown to block these increases of Aβ secretion and decrease plaque formation (Cimetiere et al, Bioorg Med Chem Lett, 1998). Therefore, Ramatroban, as a TPr antagonist, has the potential to reduce progression of Alzheimer's Disease.
Depression is common among Alzheimer's Disease patients. Prostaglandin D2 is the most common prostaglandin in the brain and it known for its role in sleep/wake regulation (Urade et al, Sleep Med Rev, 2011). Prostaglandin D2 exerts its effects on two receptors, the DPr1 and DPr2 receptors. Through the DPr2 receptor, prostaglandin D2 induces depression symptoms while blockade with Ramatroban (a DPr2 antagonist) restores social interaction and novel object exploration (Haba et al, J Neurosci, 2014). Ramatroban has the potential to reduce depression in Alzheimer's Disease patients.
Parkinson's disease is a progressive neurodegenerative disorder characterized by symptoms including tumors, bradykinesia, rigidity and postural instability. It is well established that that the underlying pathological explanation for these traits is the selective death of dopaminergic neurons in the substantia nigra of the brain. Neuronal cell death is also caused by the accumulation of abnormal aggregates of alpha synuclein proteins, a structural element of Lewy bodies, within the nerve cell. Furthermore, aging associated with reduced mitochondrial activity and oxidative stress also contribute to Parkinson's development.
Aging, which is a risk factor for many neurodegenerative disorders, is associated with platelet hyperactivation and release of extracellular vesicles that account for 70-90% of blood circulating vesicles. Age related platelet activity is due to elevated levels of thromboxane A2 (TxA2) that activate platelets through the TxA2 receptor (TPr). In Parkinson's, platelets release reactive oxygen species (ROS) that produce cellular lesions, damage and cell death. ROS also contributes to mitochondrial dysfunction, an organelle critical for energy generation, leading to neuronal cell death and neurodegeneration.
In addition to oxidative stress, TxA2 has been shown to induce direct neuronal cell loss of the dopaminergic neurons (Yagami et al, Neurobiol Dis, 2004).
Oxidative stress and hypoxia lead to increased prostaglandin D2 in the brain (Taniguchi et al, J Neurosci, 2007). Through the DPr2 receptor, prostaglandin D2 can promote the transition from acute to chronic neurodegeneration which contributes to Parkinson's development (Corwin et al, J Neuroinflammation, 2018). Therefore, by blocking the DPr2 receptor, Ramatroban may prevent neurodegeneration and development of Parkinson's Disease.