Increased Susceptibility to Ischemic Brain Injury in Cyclooxygenase-1–Deficient Mice

Abstract

Cyclooxygenase-1 (COX-1), a rate-limiting enzyme in the synthesis of prostanoids, is involved in selected vasodilatatory responses of the cerebral circulation. Cyclooxygenase-1-null mice were used to determine whether COX-1 influences cerebral ischemic damage. The middle cerebral artery was occluded in COX-1 -/- and +/+ mice (n = 9/group), and lesion volume was determined in thionin-stained sections 24 or 96 hours later. Middle cerebral artery occlusion produced larger infarcts in COX-1 -/- mice, both at 24 (35 +/- 17%; P < 0.05) and 96 hours (41 +/- 16%; P < 0.05) after ischemia. The enlargement was not due to increased susceptibility to glutamate excitotoxicity, because microinjection of N-methyl-D-aspartate or kainate in the parietal cortex produced comparable lesions in COX-1 +/+ and -/- mice ( P > 0.05; n = 8/group). To examine the contribution of hemodynamic factors to the enlargement of the infarct, cerebral blood flow was monitored by laser-Doppler flowmetry in the ischemic territory (n = 6/group). Although the reduction in cerebral blood flow was comparable in the ischemic core ( P > 0.05), at the periphery of the ischemic territory the reduction was greater in COX-1 -/- mice (-58 +/- 4%) than in COX-1 +/+ mice (-34 +/- 5%; P < 0.05). It is concluded that mice lacking COX-1 are more susceptible to focal cerebral ischemia, an effect that can be attributed to a more severe cerebral blood flow reduction in vulnerable regions at the periphery of the ischemic territory. Thus, the vascular effects of COX-1 may contribute to maintain cerebral blood flow in the postischemic brain and, as such, play a protective role in ischemic brain injury.

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

“…In our stroke model, the infarct volume in vehicle-treated Cox1 À / À mice was similar as in Cox1 þ / þ animals in line with some but not all previous studies (Fig. 7c) [28][29][30] . Interestingly, nicotinic acid had no effect on the infarct volume in Cox1 À / À mice, whereas Cox1 þ / þ littermates were protected (Fig.…”

The inflammatory response in stroke

“…COX-1 is constitutively expressed in many cells types, including microglia and leukocytes during brain injury . COX-1 deficient mice have increased vulnerability to brain ischemia, and would support a protective role possibly due to an effect on maintaining cerebral blood flow (Iadecola et al, 2001b). However, conflicting data exist.…”

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…First, it is quite clear that oxidative stress due to excessive levels of reactive oxygen species is a major mechanism of poststroke brain injury. Studies of stroke in mice either overexpressing antioxidants or deficient in pro-oxidant enzymes have reported smaller infarct volumes than in wild-type controls (Iadecola et al, 1997(Iadecola et al, , 2001Kinouchi et al, 1991;Sampei et al, 2000;WeisbrotLefkowitz et al, 1998;Yang et al, 1994), and conversely, studies of antioxidant-deficient mice have found larger infarcts (Crack et al, 2001;Kondo et al, 1997;Murakami et al, 1998). Moreover, several studies in Nox2-deficient mice have reported substantially smaller infarct and edema volumes, and less blood-brain barrier disruption than wild-type controls, pointing to Nox2 oxidase as a key source of damaging superoxide in the brain after stroke (Chen et al, 2009;Jackman et al, 2009;Kahles et al, 2007;Kunz et al, 2007;Walder et al, 1997).…”