L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria

Abstract

Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.

Whole blood transfusion improves vascular integrity and increases survival in artemether-treated experimental cerebral malaria

“…Since Ang-2 has been proposed as a risk factor for cognitive injury in pediatric CM, this finding is of critical importance, indicating that fresh blood counteracts the ECM-related inflammation and vascular insult. These findings are in line with data showing that interventions that counteract vascular dysfunction and inflammation are beneficial in ECM 32 , 40 , 41 , 46 – 48 . It is noteworthy, however, that the improvement in Ang-2 levels by transfusion was observed at 24 but not at 6 h, indicating that the intervention takes time to show benefit on this parameter.…”

“…The procedure was performed as previously described 32 . Six hours after treatment, mice were anesthetized with urethane (2 mg/g ip) with final volume 100 µL per animal.…”

Whole blood transfusion improves vascular integrity and increases survival in artemether-treated experimental cerebral malaria

“…The procedure was performed as previously described 25 . Six hours after treatment, mice were anesthetized with urethane (2 mg/g ip) with nal volume 100 µL per animal.…”

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

“…Further, TXA2 has been reported to produce endothelial dysfunction by activation and release of inflammatory cytokines [27–29]. Moreover, TXA2 synthase inhibitor has shown to improve endothelial function and cerebral blood flow in experimental animals [30]. However, there is no conclusive study on efficacy of selective TXA2 synthase inhibitor in memory impairment and dementia.…”