Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: the possible molecular mechanism

Brain Res. 2013 Nov 13;1538:93-103. doi: 10.1016/j.brainres.2013.09.036. Epub 2013 Sep 29.


Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. Recent studies have demonstrated that animals housed in an enriched environment condition after an experimental stroke obtained a better functional outcome than those housed in a standard condition. However, little is known about the underlying mechanisms of neuroprotective effects of enriched environment exposure prior to injury. The current study examined the neuroprotective effects of prior enriched environment exposure after transient middle cerebral artery occlusion (MCAO) in rats. Male Sprague Dawley (SD) rats, weighing 55-65g at the beginning of the experiment, were randomly assigned to a pre-ischemic enriched environment (PIEE) or pre-ischemic standard condition (PISC) group for 1 month. They were weighed on days1, 7, 18, and 28, and their locomotor activity was tracked during the period between 9:00am and 3:00pm daily. After 1 month, ischemia was induced by occluding the middle cerebral artery for 90min, followed by reperfusion. After approximately 24h of the operation, functional outcomes were assessed using the beam-walking test and a neurological evaluation scale in all rats. We measured the expression of extracellular signal regulated protein kinases1/2 (ERK1/2) by western blotting and gene expression levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthasen (iNOS) by Real-Time PCR in the cortical area affected by ischemia. Finally, we measured the level of malondialdehyde (MDA) content, which is a biomarker of oxidative stress. The results showed that rats in the PIEE group had lighter weight than those in the PISC group. The functional outcomes of rats in the PIEE group were better than those in the PISC group, and substances associated with inflammation, such as MDA, nNOS, iNOS, and phospho-ERK1/2, were lower in the PIEE group compared with the PISC group. These results indicate that enriched environment may provide neuroprotection via ischemic preconditioning and enhance resilience to cerebral ischemia.

Keywords: BIT; Cerebral ischemia; ERK1/2; Enriched Environment; MDA; PIEE; PISC; brain ischemic tolerance; extracellular signal regulated protein kinases1/2; iNOS; inducible nitric oxide syntheses; malondialdehyde; nNOS; nNOs; neuronal nitric oxide syntheses; p-ERK1/2; phosphorylated extracellular signal regulated protein kinases1/2; pre-ischemic enriched environment; pre-ischemic standard condition; tMCAO; transient middle cerebral artery occlusion..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Body Weight / physiology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / physiopathology
  • Environment*
  • Male
  • Malondialdehyde / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitric Oxide Synthase / metabolism
  • Oxidative Stress
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / physiopathology


  • Malondialdehyde
  • Nitric Oxide Synthase
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3