Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for ...anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
Traumatic brain injury (TBI) is a leading cause of death and disability in young adults worldwide. TBI survival is associated with persistent neuropsychiatric and neurological impairments, including ...posttraumatic epilepsy (PTE). To date, no pharmaceutical treatment has been found to prevent PTE or ameliorate neurological/neuropsychiatric deficits after TBI. Brain trauma results in immediate mechanical damage to brain cells and blood vessels that may never be fully restored given the limited regenerative capacity of brain tissue. This primary insult unleashes cascades of events, prominently including neuroinflammation and massive oxidative stress that evolve over time, expanding the brain injury, but also clearing cellular debris and establishing homeostasis in the region of damage. Accumulating evidence suggests that oxidative stress and neuroinflammatory sequelae of TBI contribute to posttraumatic epileptogenesis. This review will focus on possible roles of reactive oxygen species (ROS), their interactions with neuroinflammation in posttraumatic epileptogenesis, and emerging therapeutic strategies after TBI. We propose that inhibitors of the professional ROS-generating enzymes, the NADPH oxygenases and myeloperoxidase alone, or combined with selective inhibition of cyclooxygenase mediated signaling may have promise for the treatment or prevention of PTE and other sequelae of TBI.
This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
•Reactive oxygen species (ROS) and neuroinflammation contribute to the secondary injury after traumatic brain injury (TBI).•ROS-induced cytotoxicity and dysregulation of redox-regulated processes both contribute to secondary injury after TBI.•Oxidative stress / ROS generation and inflammation are highly interdependent and mutually reinforcing after TBI.•Targeting both ROS generation and inflammation may synergize to reduce secondary injury and prevent epilepsy after TBI.
This review describes an adult rat model of status epilepticus (SE) induced by diisopropyl fluorophosphate (DFP), and the beneficial outcomes of transient inhibition of the prostaglandin-E2 receptor ...EP2 with a small molecule antagonist, delayed by 2–4 h after SE onset. Administration of six doses of the selective EP2 antagonist TG6-10-1 over a 2–3 day period accelerates functional recovery, attenuates hippocampal neurodegeneration, neuroinflammation, gliosis and blood-brain barrier leakage, and prevents long-term cognitive deficits without blocking SE itself or altering acute seizure characteristics. This work has provided important information regarding organophosphate-induced seizure related pathologies in adults and revealed the effectiveness of delayed EP2 inhibition to combat these pathologies.
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Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain ...inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague–Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80–150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.
•DFP-induced SE in rats causes neuroinflammation, neurodegeneration and weight loss.•TG6-10-1 blunted neuroinflammation and microgliosis, but not astrogliosis.•Neurodegeneration and weight loss were attenuated by TG6-10-1.•EP2 antagonist TG6-10-1 did not alter DFP-induced behavioral seizures.
The azaindole chemical scaffold is represented in many biologically active natural products and synthetic derivatives. Recently, this chemical scaffold yielded several therapeutic agents for a ...variety of diseases. Due to the interesting biochemical and biophysical properties of various isomeric azaindoles, numerous investigators have designed and implemented novel synthetic methods for azaindole core units in the past few decades. By using these novel strategies, a number of diversely substituted azaindoles including bioactive natural products, key intermediates and drug candidates have been produced. Herein, we have reviewed the novel synthetic strategies developed for azaindoles since 2011 and highlight their attractive reaction mechanisms, advantages and their limitations. This review may offer potential solutions to develop novel and facile methodologies for the azaindole derivatives of biological interest.
Cyclooxygenase‐2 in epilepsy Rojas, Asheebo; Jiang, Jianxiong; Ganesh, Thota ...
Epilepsia (Copenhagen),
January 2014, Letnik:
55, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
Epilepsy is one of the more prevalent neurologic disorders in the world, affecting approximately 50 million people of different ages and backgrounds. Epileptic seizures propagating through ...both lobes of the forebrain can have permanent debilitating effects on a patient's cognitive and somatosensory brain functions. Epilepsy, defined by the sporadic occurrence of spontaneous recurrent seizures (SRS), is often accompanied by inflammation of the brain. Pronounced increases in the expression of key inflammatory mediators (e.g., interleukin ‐1β IL‐1β, tumor necrosis factor alpha TNFα, cyclooxygenase‐2 COX‐2, and C‐X‐C motif chemokine 10 CXCL10) after seizures may cause secondary damage in the brain and increase the likelihood of repetitive seizures. The COX‐2 enzyme is induced rapidly during seizures. The increased level of COX‐2 in specific areas of the epileptic brain can help to identify regions of seizure‐induced brain inflammation. A good deal of effort has been expended to determine whether COX‐2 inhibition might be neuroprotective and represent an adjunct therapeutic strategy along with antiepileptic drugs used to treat epilepsy. However, the effectiveness of COX‐2 inhibitors on epilepsy animal models appears to depend on the timing of administration. With all of the effort placed on making use of COX‐2 inhibitors as therapeutic agents for the treatment of epilepsy, inflammation, and neurodegenerative diseases there has yet to be a selective and potent COX‐2 inhibitor that has shown a clear therapeutic outcome with acceptable side effects.
Introduction：A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory ...reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury.
Areas covered: Here we describe the roles of COX-2 as a major inflammatory mediator. In addition, we discuss the receptors for prostanoids PGE
2
, prostaglandin D2, and PGF
2α
as potential therapeutic targets for inflammation-driven diseases. The consequences of prostanoid receptor activation after seizure activity are discussed with an emphasis on the utilization of small molecules to modulate prostanoid receptor activity.
Expert opinion: Limited clinical trial experience is supportive but not definitive for a role of the COX signaling cascade in epileptogenesis. The cardiotoxicity associated with chronic coxib use, and the expectation that COX-2 inhibition will influence the levels of endocannabinoids, leukotrienes, and lipoxins as well as the prostaglandins and their endocannabinoid metabolite analogs, is shifting attention toward downstream synthases and receptors that mediate inflammation in the brain.
Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a ...potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.
The diastereoselective synthesis of highly substituted pyrrolidines has been accomplished using a six‐carbon building block bearing carbon atoms with different reactivities. In this reaction, the ...building block acts a 1,3‐dipole and undergoes cyclization with imines formed in situ to give pyrrolidine derivatives.
Highly functionalized pyrrolidine and γ‐lactam derivatives were synthesized using a six‐carbon building block.
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