Cilostazol in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting about 1% of the elderly population, with 5 to over 35 new cases in 100,000 per year diagnosed with PD, with a prevalence of over 10 million people worldwide. This number is projected to increase to more than 12 million by 2040. The incidence of PD increase with age but it can affect people less than 50 years old. In the Eastern Mediterranean Region (EMR), the prevalence rate of PD increased by 42.3% over the period 1990-2016, and reached 87.1 per 100,000 in 2016. Factors that cause PD are multifactorial including genetic predispositions, environmental toxins, and aging leading to disease initiation and progression.

Parkinson's disease is a chronic condition characterized by the slow progression of the dopaminergic neuronal degeneration with irreversible loss of dopamine (DA). It is associated with motor symptoms as bradykinesia, resting tremor, rigidity, and postural instability. It also affects other extra-nigral dopaminergic, cholinergic and serotoninergic tracts, leading to non-motor symptoms as anosmia, sleep disorders and constipation as well as cognitive and psychiatric symptoms like cognitive impairment, dementia and depression.

Cognitive decline is a common non-motor symptom in PD, and an important source of patient disability and caregiver burden. The pathophysiology of cognitive impairment in PD is complex and likely involves a disruption of several distinct neuronal networks occurring over time. The timing, profile and rate of cognitive decline vary widely among individuals with PD and can range from normal cognition to mild cognitive impairment and dementia.

The pathogenesis of PD is not fully understood, however, several studies have revealed that the inflammation, oxidative stress, and neuronal apoptosis have a major role in its progression. In addition, PD was found to be linked with the reduction of the regional cerebral blood flow (rCBF). This reduced cerebral blood flow has been found to be associated with the occurrence of cognitive impairment and dementia.

Neuroinflammation in PD has been evidenced through several human and animal studies. It may result from the consequences of ongoing neuronal cell death in PD, the aggregation of misfolded α-Synuclein, microgliosis and astrogliosis, peripheral inflammation and PD-risk-associated genes. Any of these factors will result in the activation of microglia, CNS-resident macrophages important for normal CNS functioning, and production of pro-inflammatory mediators as cytokines (IL1, IL6, and TNFα) chemokines and reactive oxygen species, leading to the exacerbation of DA neuron degeneration.

In addition, PD has been linked to decreased levels of brain-derived neurotrophic factor (BDNF). Brain-derived neurotrophic factor belongs to a family of proteins called neurotrophin family of growth factors, that support differentiation, maturation, and survival of neurons in the nervous system and shows a neuroprotective effect under adverse conditions, such as glutamatergic stimulation, cerebral ischemia, hypoglycemia, and neurotoxicity. Studies has investigated the reduced expression of BDNF through the decreased levels of BDNF in the substantia nigra pars compacta in post-mortem brain tissues, and decreased serum levels of BDNF in PD patients. These reduced levels of BDNF have been attributed to the inflammation and neurodegeneration.

Oxidative stress along with inflammation has been evidenced to play a critical role in the dopaminergic neuronal degeneration. The sources and mechanisms for generation of reactive oxygen species (ROS) include dopamine metabolism, mitochondrial dysfunction, iron, neuroinflammation, calcium, and aging. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system, the main pathway through which cells degrade and remove damaged and unwanted proteins, and mitophagy are affected by oxidative stress. Together, these various mechanisms contributes to the neurodegeneration in PD where primary insults lead to oxidative stress, which damages key cellular proteins and the disruption of lipid membranes causing more ROS production. The role of oxidative stress is supported by postmortem brain analyses showing increased levels of 4-hydroxyl-2-nonenal (HNE), a by-product of lipid peroxidation, and DNA and RNA oxidation products 8-hydroxy-deoxyguanosine and 8-hydroxy-guanosine. In addition, oxidative stress has been found to be involved in the pathway leading to apoptotic cell death which has been investigated through research studies involving human and animal PD models.

In addition, neuroinflammation and oxidative stress have been found to contribute to the development of cognitive impairment in PD patients.

For many years, the conventional treatment for PD has included dopaminergic treatment as Levodopa\carbidopa or dopamine agonists, anti-cholinergics, MAOI, catechol-o-methyl transferase (COMT) inhibitors, and amantadine. Although these options have been found to be effective, they could only improve the disease symptoms, but do not modify the disease progression. Hence, researchers have focused on developing disease-modifying agents to stop or slow the progression acting as neuroprotective agents. Since the inflammation and oxidative stress play an important role in the pathophysiologic progression of PD, recent studies have investigated the mitigation of the disease pathology through anti-inflammatory and anti-oxidant agents. Human and animal studies have found that the anti-inflammatory agents protect dopaminergic neurons and ameliorate the disease associated symptoms. Several anti-oxidant agents, such as curcumin and vitamin E, have been investigated in PD patients. These agents have shown an effect on reducing dopamine oxidation, delaying the disease progression, and reducing the motor deficit. Therefore, more treatment options attempting to stop the pathophysiologic alterations should be explored.

Cilostazol (CSZ), a 2-oxo-quinoline derivative, is a selective inhibitor of phosphodiesterase-3 that increases intracellular cAMP levels and activates protein kinase A. Cilostazol is a lipophilic drug that can cross the blood brain barrier, with anti-platelet, anti-mitogenic, and vasodilating properties, and is FDA approved for the treatment of ischemic symptoms of peripheral vascular diseases, including intermittent claudication, and the prevention of cerebral and myocardial infarction. In addition, cilostazol improves the cerebral blood flow and cerebral function during the chronic stage of cerebral infarction. Recently, it has noteworthy antioxidant, anti-inflammatory, and anti-apoptotic properties.

Cilostazol has shown potent anti-inflammatory action through inhibiting toll-like receptor (TLR) signaling-mediated NF-κB activation and the production of pro-inflammatory cytokine as IL-6, prostaglandin E2, interleukin-1 (IL-1), tumor necrosis factor (TNF-α), and monocyte chemo-attractant protein-1 (MCP-1). It can also exert its antioxidant effects through reversing the GSH depletion, normalizing hippocampal oxidative stress biomarkers as Glutathione peroxidase and superoxide dismutase, and reducing the MDA levels. Several studies have demonstrated that cilostazol has neurotrophic effect through improving the expression of neurotrophic factors, and in turn, it increases the levels of BDNF.

Cilostazol has been used in experimental studies for several neurodegenerative disorders as Parkinson's disease, Huntington disease, and Alzheimer's disease (AD) for its neuroprotective effect due to its neuroprotective effect. This neuroprotective effect has been demonstrated through maintaining the brain function in animal models with focal cerebral ischemia attributed to its anti-apoptotic properties, and preventing the hypoperfusion-induced cognitive impairment in animal models with vascular dementia. In addition, it has beneficial effects on cognitive and regional cerebral blood flow (rCBF) deficits in the elderly patients, and is associated with a decreased risk of dementia, and slowing the rate of cognitive decline on the MMSE in mild cognitive impairment patients, mild dementia patients, and Alzheimer's disease patients. From the previously mentioned data, cilostazol can act as a potential candidate for PD patients.

Cilostazol has been evaluated in 2 animal studies and it was found that cilostazol possessed an anti-inflammatory, anti-oxidant, and anti-apoptotic effects in PD through dampening NF-κB, and its downstream effectors including TNF-α and IL-1β, reversing the activation of glycogen synthase kinase-3 β (GSK-3β), a pivotal effector in neuronal apoptosis, contributes preserving dopaminergic neuron integrity clarifying the enhanced motor activity, activating nuclear factor erythroid-related factor 2/ heme oxygenase 1 (Nrf2/HO-1), suppressing High mobility group box 1 protein/Toll-like receptor 4 (HMGB1/TLR4) axis, and upregulatig Phosphoinositide 3-kinases/ Protein kinase B (PI3K/Akt) besides mammalian target of rapamycin (mTOR) inhibition.

Cilostazol has a good safety profile beside its potent anti-inflammatory and antioxidant effects, which make it a candidate for many experimental and clinical trials. Its more common side effects include headache (27-34%) and GI symptoms (12-19%). It has other side effects as ecchymoses, anemia, edema, dizziness, palpitations, rhinitis, pharyngitis, chest pain, allergy, myalgia, and sleep disturbance, but they are less common (<2%).