Neuroprotection Induced by Energy and Protein-Energy Undernutrition Is Phase-Dependent After Focal Cerebral Ischemia in Mice

Abstract

Malnutrition predisposes to poor stroke outcome. In animal models, undernutrition protected against ischemic injury in some, but not in other studies. In view of diverse stroke models and food restriction paradigms, the consequences of undernutrition are poorly understood. Herein, we exposed mice to energy-reduced and protein-energy-reduced diets for 7-30 days and subsequently induced intraluminal middle cerebral artery occlusion. Undernutrition phase dependently influenced ischemic injury. Shortlasting 7 days of protein-energy undernutrition, but not energy undernutrition, decreased post-ischemic brain leukocyte infiltration and microglial activation and reduced brain Il-1β mRNA, but did not protect against ischemic injury. Fourteen days of energy and protein-energy undernutrition, on the other hand, reduced ischemic injury despite absence of anti-inflammatory effects. Anti-oxidant genes (Sod-1, Sod-2, and Cat mRNAs) were regulated in the liver and, to a lesser extent, the ischemic brain, indicating an adapted, compensated stage. Conversely, 30 days of energy and protein-energy undernutrition caused progressive animal exhaustion associated with post-ischemic hypoperfusion, rise of metabolic markers (Sirt-1 and Glut-1 mRNAs, Sirt-1 protein) in the ischemic brain, and reregulation of pro-and anti-oxidant markers (now also Nox-4 and Gpx-3 mRNAs) in the liver. In the latter condition, no neuroprotection was noted. Our study suggests an adaptation of metabolic systems that provides neuroprotection in a circumscribed time window.

Modeling undernutrition with enteropathy in mice

“…Then, there is a progressive exhaustion of the adaptive mechanisms. A similar pattern was observed in malnourished mice with focal cerebra ischemia 21 . While malnutrition for 7 to 14 days induced survival-promoting mechanisms such as a neuroprotection and immunoregulation, longer exposure to malnutrition for 30 days impairs stroke outcome 21 .…”

Hypocaloric Diet Initiated Post-Ischemia Provides Long-Term Neuroprotection and Promotes Peri-Infarct Brain Remodeling by Regulating Metabolic and Survival-Promoting Proteins

“…*p < 0.05 compared with ischemic mice on normocaloric diet (n = 12 animals/ group). Scale bars, 100 μm (in a-f) exposure for 14 days reduced neurological deficits, infarct volume, neuronal injury, and blood-brain barrier breakdown at 24 h post-MCAO, whereas prolonged hypocaloric diet exposure for 30 days failed to show neuroprotective effects probably due to compromised post-ischemic reperfusion resulting from progressive animal exhaustion [9]. The degree of calorie reduction explains different findings in this earlier and the present study.…”

“…The nutritional status of mice on this more severely hypocaloric diet was significantly compromised. The mice exhibited an intestinal malabsorption syndrome with pale stool, enlarged stool samples, and blood beddings on stool [9]. In this earlier study, hypocaloric diet Fig.…”

“…Sections were scanned and quantified using Image J software (National Institute of Health, Bethesda, MD, U.S.A.). In animals sacrificed at 3 dpi, infarct volume was measured by subtracting areas of healthy tissue of the ischemic hemisphere from those of the contralesional hemisphere [9,16]. In animals sacrificed at 56 dpi, striatum volume and whole brain volume were evaluated by analyzing ipsilesional and contralesional brain areas across the forebrain, of which percent volume ratios were determined [16].…”

“…Tissue energy requirements and oxidative stress are important factors influencing ischemic injury, neurological recovery, and brain remodeling. Experimental studies in mice and rats using models of focal cerebral ischemia by middle cerebral artery occlusion (MCAO) showed that caloric restriction or fasting prior to a stroke reduced post-ischemic neurological deficits, infarct volume, and brain inflammatory responses [3,[5][6][7][8][9]. In models of global cerebral ischemia induced by bilateral common carotid artery occlusion in rats and gerbils, caloric restriction initiated after ischemia did not influence neurological recovery and neuronal survival but increased acutephase responses and disturbed terminal axonal and synaptic plasticity [10,11].…”