Inhibition of Nitric Oxide Synthase with 7-Nitroindazole does not Modify Early Metabolic Recovery Following Focal Cerebral Ischemia in Rats

Abstract

Nitric oxide has been strongly implicated in the development of tissue infarction in response to focal cerebral ischemia. Nitric oxide and its derivatives can inhibit components of the electron transport chain, providing a likely target for these substances in ischemic and post-ischemic brain. Lactate content is increased during post-ischemic reperfusion in tissue destined to become infarcted, consistent with impairment of mitochondrial respiration. To investigate the possible involvement of nitric oxide in generating these changes, we have tested the effect of 7-nitroindazole, a nitric oxide synthase (NOS) inhibitor, on the content of lactate and other metabolites during early reperfusion following temporary focal ischemia. This treatment inhibited total NOS by approximately 50%. However, the treatment did not significantly affect the marked increases in lactate in post-ischemic brain nor did it alter the recovery of other energy-related metabolites. These findings indicate that inhibition of oxidative metabolism is probably not the primary site of the deleterious effects of nitric oxide and derivatives during early post-ischemic reperfusion.

Mitochondria, oxidative metabolism and cell death in stroke

“…Restoration of blood flow during the first 30 to 60 minutes in rats and mice greatly limits the size of the infarcts that subsequently develop [16,17] and can completely block cell loss , indicating that the development of irreversible damage in neurons and other cells in the core tissue is delayed. Even with ischemic periods up to three hours, which will ultimately lead to infarction, there is often near complete recovery of phosphocreatine (to more than 90% of pre-ischemic values) and of the adenylate energy charge (or other measures of adenine nucleotide balance) during the first two hours following reperfusion [34,36,39,45,46]. The recovery of these metabolic parameters requires the presence of intact and functional cells that at least partially regain the complex metabolic activities and control processes required to meet energy demands.…”

“…At one hour of reperfusion following two hours of ischemia in rats, glucose utilization, as assessed from deoxyglucose incorporation, is reduced to approximately 50% of normal values in tissue regions that formed the ischemic core [9]. Furthermore, the lactate content remains many times higher than in normal tissue suggesting ongoing restrictions on the oxidative metabolism of pyruvate [34,36,39,45,46]. Consistent with these results, the generation of isotopically-labelled glutamate from glucose is also markedly decreased [41,46] indicating greatly reduced neuronal energy metabolism.…”

“…Reperfusion in the penumbral tissue leads to complete or near complete recovery of phosphocreatine and the adenine nucleotide balance within the first hour of reperfusion following ischemic periods lasting up to three hours or even longer [34,39,45,46]. The restoration of ATP content is less complete, again because of slow regeneration of the depleted adenine nucleotide pool.…”

“…The inability of mitochondria to then generate ATP and the depletion of cytosolic ATP due to reversal of the ATP synthase lead to major metabolic derangements and ultimately activation of degradative enzymes leading to necrosis. At least for focal ischemia in brain, this mechanism is difficult to reconcile with the extent of recovery of energy-related metabolites during early reperfusion in core and penumbral tissue destined to become part of the infarct [34,39,45,46]. The near normal respiratory properties of mitochondria assessed in preparations from tissue early after reperfusion [16,59,60] is also at variance with induction of the permeability transition unless this was reversed during sample processing.…”

Beneficial effects of arthrocen on neuroinflammation and behavior like depression in stroke in a murine model

“…Ischemia damage is followed by systemic inflammation which subsequently causes further loss of neuronal function and cellular damage (Fang et al, 2019 ; Helps & Sims, 2007 ). Symptoms of brain ischemia damage in a large number of patients can be as depression, anxiety, and physical disabilities (Hu et al, 2021 ; Whyte & Mulsant, 2002 ).…”