Purinergic receptors as potential therapeutic targets in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognitive ability and is a serious cause of mortality. Many of the pathological characteristics associated with AD are revealed post-mortem, including amyloid-β plaque deposition, neurofibrillary tangles containing hyperphosphorylated tau proteins and neuronal loss in the hippocampus and cortex. Although several genetic mutations and risk factors have been associated with the disease, the causes remain poorly understood. Study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of disease. Therefore, AD researchers rely on in vitro studies and the use of AD animal models where neuroinflammation has been shown to be a major characteristic of AD. Purinergic receptors are a diverse family of proteins consisting of P1 adenosine receptors and P2 nucleotide receptors for ATP, UTP and their metabolites. This family of receptors has been shown to regulate a wide range of physiological and pathophysiological processes, including neuroinflammation, and may contribute to the pathogenesis of neurodegenerative diseases like Parkinson’s disease, multiple sclerosis and AD. Experimental evidence from human AD tissue has suggested that purinergic receptors may play a role in AD progression and studies using selective purinergic receptor agonists and antagonists in vitro and in AD animal models have demonstrated that purinergic receptors represent novel therapeutic targets for the treatment of AD.

Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug‐refractory epilepsy

“…Probably the most likely cause for the observed neuroprotection via UTP is a reduction in seizure severity. However, UTP or its metabolites have been frequently described to provide neuroprotective effects in the brain against various pathologic insults such as ischemia or Alzheimer's disease . It is unclear why ADP treatment did not translate into increased neurodegeneration despite exacerbating seizures.…”

Pathological overproduction: the bad side of adenosine

“…Interestingly, the initial findings of a case–control study were the first to demonstrate that caffeine/coffee consumption is associated with a reduced risk, or delayed onset, of dementia (Cao et al , ). Therefore, it seems that caffeine, the most popular and widely used drug in the world, by antagonizing the effects of adenosine, retains a big potential to counteract different neurodegenerative diseases (Woods et al , ).…”

Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor

“…3 Both P2X7 and P2X4 receptors have become a novel molecular target for treatment and PET (positron emission tomography) imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. 4 In our previous work, we have developed [ 11 C]GSK1482160 5,6 as a new PET probe for imaging of P2X7 receptor as indicated in Figure 1.…”

“…However, potent and selective P2X4 receptor antagonists are required as research tools for investigating the physiological functions of P2X4 receptor. 5-BDBD (5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e] [1,4]diazepin-2one) is a specific P2X4 receptor antagonist with an IC 50 of 500 nM in Chinese hamster ovary cells (CHO). 7 Here we report the design, synthesis, radiolabeling and preliminary biological evaluation of a series of radiolabeled 5-BDBD analogs as new candidate P2X4 receptor radioligands as shown in Figure 2.…”