Neurological Disease

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Millions of people are affected by neurological diseases and disorders worldwide which severely impairs their daily function and quality of life. For decades, the underlying mechanisms of many neurological disorders remained a mystery. However, emerging evidence is shedding light upon potential targets in neurological diseases, including Alzheimer's disease and Parkinson's disease which will help advance and broaden the scope of effective treatments. 

Alzheimer's Disease

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 the pathogenesis of Alzheimer's. 

Mechanisms:

A hallmark of Alzheimer’s disease (AD) brain is the deposition of Tau protein (TauP) and senile plaques comprising amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain undergoes oxidative stress leading to release of oxidized mediators that activate the thromboxane A2 receptor (TPr). TPr activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TPr antagonists have been shown to block these increases of Aβ secretion and decrease plaque formation (Cimetiere et al, Bioorg Med Chem Lett, 1998).

 

TPr is expression on platelets and is stimulated with thromboxane A2 (TxA2) leading to platelet activation and thrombosis. 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). This is consistent with presence of Aβ in the skin after blood clotting. Platelets also release Tau proteins, another diagnostic tool of Alzheimer's (Mukaetova-Ladinska et al, Curr Alzheimer Res, 2018). Therefore, TPr induced platelet activation risks development of Aβ and TauP related disorders including AD especially in patients with cardiovascular disease and high thromboxane A2.

As a TPr antagonist, Ramatroban will potentially reduce accumulation of Aβ plaque in the brain by inhibiting platelet activation during inflammatory conditions that contribute to the progression of Alzheimer's including cardiovascular disease.

Parkinson's Disease

Parkinson's disease is a progressive neurodegenerative disorder characterized by symptoms including tumors, bradykinesia, rigidity and postural balance. 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 reduce 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 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. 

ROS generation leads to hypoxia which increases prostaglandin (PG)D2 in the brain, 90-fold (Taniguchi et al, J Neurosci, 2007). PGD2 exerts its functions through two receptors, the DPr1 and DPr2 receptors. PGD2 is metabolized into PGJ2 which, in turn, stimulates the DPr2 receptor, promoting the transition from acute to chronic neurodegeneration that contributes to Parkinson's development (Corwin et al, J Neuroinflammation, 2018). This is consistent with Parkinson's disease-like pathology in mice following PGJ2-microinfusions into the brain (Pierre et al, Neuroinflammation, 2009). Therefore, antagonism of the DPr2 receptor with Ramatroban will help mitigate neuroinflammation and reduce the rate of developing neurodegenerative disorders, including Parkinson's disease. 

Release of Aβ from platelets leads to direct upregulation of TxA2 in the brain which induces neuronal cell loss of the dopaminergic neurons (Yagami et al, Neurobiol Dis, 2004). However, the association of Alzheimer's disease pathology characterize by Aβ accumulation with the development of Parkinson's diseases remains unclear. 

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