Chronic Administration of Lamotrigine Downregulates COX-2 mRNA and Protein in Rat Frontal Cortex

Abstract

Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A(2) (PLA(2)) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA(2) isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder.

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease

“…253 Pending definitive studies on this topic, one might speculate that the anti-inflammatory effects of these medications, or other yet unknown pharmacological properties, may partially mitigate their adverse effects on traditional CVD risk factors. 96,[254][255][256][257] Although it remains possible that psychotropic medications contribute in part to CVD risk in MDD and BD, there are 3 primary reasons to conclude that MDD and BD are moderate-risk conditions independent of the effect of psychotropic medications and that medications should not be the only focus. First, the strongest evidence regarding these medications relates to increased CVD risk factors, and the best available evidence suggests that the association between mood disorders and CVD is independent of CVD risk factors.…”

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

“…168 Upon chronic administration to produce therapeutically relevant plasma levels in rats, lamotrigine did not decrease the turnover of AA in their brain phospholipids; 169 however, it downregulated COX-2 mRNA and protein expression. 170 Lamotrigine's ability to downregulate COX-2 may be related to its effectiveness in delaying the onset of depressive symptoms 164,165 or in managing symptoms in rapid cycling bipolar disorder. 166,167 After testing candidate drugs at the preclinical level, PET with 11 C-labeled AA and DHA could be used to study the metabolism of these polyunsaturated fatty acids in bipolar disorder patients and to proxy the effectiveness of candidate drugs in healthy humans.…”

Anti-Stress Effects of Mood Stabilizers and Relevance to Their Therapeutic Actions

“…On the other hand, it is known that chronic treatment with lithium, carbamazepine, and valproate at therapeutically relevant doses decrease arachidonic acid turnover and the level of COX-2 and prostaglandin E 2 (PGE 2 ) in the rat brain (Chang et al, 1996;Rao et al, 2008). Lithium and carbamazepine reduce the AP-2 binding activity, which leads to decreased transcription, translation and activity of arachidonic acid-specific and calcium dependent phospholipase A 2 (cPLA 2 ) (Bosetti et al, 2003;Rao et al, 2008), a PLA 2 isoform specific for release of arachidonic acid from membrane phospholipids of the brain, whereas valproate inhibits long chain acyl-CoA synthetase and thus decreases the arachidonic acid turnover (Rao et al, 2008).…”

“…Lithium and carbamazepine reduce the AP-2 binding activity, which leads to decreased transcription, translation and activity of arachidonic acid-specific and calcium dependent phospholipase A 2 (cPLA 2 ) (Bosetti et al, 2003;Rao et al, 2008), a PLA 2 isoform specific for release of arachidonic acid from membrane phospholipids of the brain, whereas valproate inhibits long chain acyl-CoA synthetase and thus decreases the arachidonic acid turnover (Rao et al, 2008). However, chronic treatment with lithium does not affect COX-1 or Ca 2+ -independent PLA 2 (Bosetti et al, 2002).…”

“…Major signaling cascades regulated by mood stabilizers are brain derived neurotrophic factor (BDNF)and extracellular signal-regulated kinase (ERK) pathways, glycogen synthase kinase-3 (GSK-3) mediated pathway, and regulating pathways for bcl-2 expression Shaltiel et al, 2007). In addition, regulation of arachidonic acid cascade by mood stabilizers is considered to be another common mechanism of action of mood stabilizers (Rao et al, 2008).…”