3-Nitropropionic Acid-Induced Ischemia Tolerance in the Rat Brain is Mediated by Reduced Metabolic Activity and Cerebral Blood Flow

Abstract

Tissue tolerance to ischemia can be achieved by noxious stimuli that are below a threshold to cause irreversible damage ('preconditioning'). Understanding the mechanisms underlying preconditioning may lead to the identification of novel therapeutic targets for diseases such as stroke. We here used the oxidative chain inhibitor 3-nitropropionic acid (NPA) to induce ischemia tolerance in a rat middle cerebral artery occlusion (MCAO) stroke model. Cerebral blood flow (CBF) and structural integrity were characterized by longitudinal magnetic resonance imaging (MRI) in combination with behavioral, histologic, and biochemical assessment of NPA-preconditioned animals and controls. Using this approach we show that the ischemia-tolerant state is characterized by a lower energy charge potential and lower CBF, indicating a reduced baseline metabolic demand, and therefore a cellular mechanism of neural protection. Blood vessel density and structural integrity were not altered by NPA treatment. When subjected to MCAO, preconditioned animals had a characteristic MRI signature consisting of enhanced CBF maintenance within the ischemic territory and intraischemic reversal of the initial cytotoxic edema, resulting in reduced infarct volumes. Thus, our data show that tissue protection through preconditioning occurs early during ischemia and indicate that a reduced cellular metabolism is associated with tissue tolerance to ischemia.

Non-toxic engineered carbon nanodiamond concentrations induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells

“…This indicates a state of energy penalty caused by imbalance in the main mitochondrial function that is to provide adequate ATP supply to ensure all the energy consuming reactions within cells. Malfunctioning of mitochondria was clearly evidenced by the decrease in the ATP/ADP ratio (Table 1 ), which is considered a good indicator of the mitochondrial phosphorylating capacity 32 , 44 . The imbalance in energy metabolism caused by mitochondrial malfunctioning observed in our experiments was strongly reinforced by data referring to the decrease in triphophate nucleotides GTP, UTP, and CTP, accompanied by the increase in their corresponding di- and monophosphate forms (Table 2 ), indicating a generalized depletion of high energy compounds leading to significant cell energy crisis.…”

Non-coding RNAs and neuroprotection after acute CNS injuries

“…Furthermore, inhibiting these miRNAs increased global protein SUMOylation that is thought to be critical for ischemic tolerance (Lee et al, 2012). Many pharmacological agents including 3-nitropropionic acid, lipopolysaccharide, estrogen, resveratrol and volatile anesthetics like isoflurane and sevoflurane are known to induce ischemic tolerance (Bracko et al, 2014; Vartanian et al, 2011; Raval et al, 2016; Koronowski et al, 2015; Lopez et al, 2016; Yan et al, 2016; Wang et al, 2011a). MiRNAs were thought to mediate the ischemic tolerance by some of these agents.…”

Fusion or Fission: The Destiny of Mitochondria In Traumatic Brain Injury of Different Severities

“…It is well known that dysfunctional mitochondria are a common feature not only of chronic neurodegenerative diseases such as multiple sclerosis 25 , Alzheimer’s disease 26 , amyotrophic lateral sclerosis 27 , Parkinson’s disease 28 , but also of acute neurodegeneration caused by cerebral ischemia 29 and traumatic brain injury (TBI) 30 – 32 . TBI is a major health and socioeconomic problem throughout the world in adults below 40 years of age.…”