Cyclooxygenase in epilepsy: from perception to application

Abstract

Cyclooxygenase (COX) catalyzes the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin and thromboxanes. The COX enzyme is a major target of nonsteroidal antiinflammatory drugs. Two isoforms of COX enzymes have been identified: the constitutively expressed COX-1 and the inducible, highly regulated COX-2. Recently, COX has been found to be expressed in different areas of the brain, and inhibitors of COX enzyme(s), particularly the COX-2 inhibitors, may attenuate inflammation associated with brain disorders. Although COX-1 is constitutively expressed in different areas of brain, there has been a conceptual neglect of the role of COX-1 inhibitors in various neurodegenerative and neuropsychiatric disorders. The present review summarizes the current understanding of COX expression in the central nervous system and the effects of COX inhibitors (both nonselective and selective COX-2 inhibitors) in epilepsy. It is speculated that COX inhibition will be a useful ameliorative adjunct in the management of epilepsy and related disorders.

Astrocyte immune responses in epilepsy

“…Acute seizures induced in rodents (following intracerebral application of kainate or bicuculline, or electrically induced status epilepticus) were shown rapidly to upregulate prototypical inflammatory cytokines in microglia and astrocytes in the brain areas where seizures originate and spread; as a consequence of this event, a downstream cascade of inflammatory mediators is transcriptionally upregulated in brain tissue similar to what has been shown in human epilepsy Gorter et al, 2006;Vezzani et al, 1999Vezzani et al, , 2000; reviewed by (Kulkarni and Dhir, 2009;Vezzani et al, 2008aVezzani et al, , 2011b]. Activation of astrocytes in the absence of neuronal degeneration has been reported in a kindling model (Khurgel et al, 1995) and induction of GFAP has been observed even after a single electroconvulsive seizure (Steward et al, 1992).…”

Immunity and Inflammation in Epilepsy

“…IL-1b, TNF-a, and IL-6 and prostaglandins, such as PGE2 and PGF2a, modify voltage-and receptor-gated ion channel function via rapid activation of posttranslational mechanisms in neurons involving protein kinases (Viviani et al 2007;Kulkarni and Dhir 2009;Vezzani et al 2013b). Cytokines also promote changes in neuronal glutamate (N-methyl-D-aspartate [NMDA] and AMPA) and g-aminobutyric acid (GABA) A receptor expression, and alter their molecular subunit composition by activating protein kinases (Stellwagen et al 2005;Balosso et al 2009).…”

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

“…Various pharmacological studies targeting IL-1β/IL-1R1, HMGB1/TLR4, COX-2/prostaglandins or the complement system have demonstrated that these inflammatory pathways significantly contribute to the onset and/or recurrence of acute brief seizures provoked by various convulsive stimuli in adult rodents [76,77,107–109]. This pharmacological evidence has been substantiated by changes in intrinsic seizure susceptibility of transgenic mice with functional alterations in these pathways [52,77,110].…”