Abstract
Cerebral ischemia/reperfusion (I/R) injury causes cognitive deficits, excitotoxicity, neuroinflammation, oxidative stress and brain edema. Vitamin K2 (Menaquinone 4, MK-4) as a potent antioxidant can be a good candidate to ameliorate I/R consequences. This study focused on the neuroprotective effects of MK-4 for cerebral I/R insult in rat’s hippocampus. The rat model of cerebral I/R was generated by transient bilateral common carotid artery occlusion for 20 min. Rats were divided into control, I/R, I/R+DMSO (solvent (1% v/v)) and I/R+MK-4 treated (400 mg/kg, i.p.) groups. Twenty-four hours after I/R injury induction, total brain water content, superoxide dismutase (SOD) activity, nitrate/nitrite concentration and neuronal density were evaluated. In addition to quantify the apoptosis processes, TUNEL staining, as well as expression level of Bax and Bcl2, were assessed. To evaluate astrogliosis and induced neurotoxicity by I/R GFAP and GLT-1 mRNA expression level were quantified. Furthermore, pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α were measured. Seven days post I/R, behavioral analysis to quantify cognitive function, as well as Nissl staining for surviving neuronal evaluation, were conducted. The findings indicated that administration of MK-4 following I/R injury improved anxiety-like behavior, short term and spatial learning and memory impairment induced by I/R. Also, MK-4 was able to diminish the increased total brain water content, apoptotic cell density, Bax/ Bcl2 ratio and GFAP mRNA expression following I/R. In addition, the high level of nitrate/nitrite, IL-6, IL-1β and TNF-α induced by I/R was reduced after MK-4 administration. However, MK-4 promotes the level of SOD activity and GLT-1 mRNA expression in I/R rat model. The findings demonstrated that MK-4 can rescue transient global cerebral I/R consequences via its anti-inflammatory and anti-oxidative stress features. MK-4 administration ameliorates neuroinflammation, neurotoxicity and neuronal cell death processes and leads to neuroprotection.
Highlights
Transient global cerebral ischemia/reperfusion (I/R, restoration of blood flow) injury is a major consequence of cardiac arrest period and resuscitation [1]
We investigated the effects of MK-4 administration on oxidative stress, neuroinflammation, cell death and subsequent short- and long-term learning and memory deficits induced by transient global cerebral I/R in vivo
The time spent in the center zone was significantly increased in I/R animals which received MK-4 (28.56 s), as the phenotype in this group was comparable with control group (one-way ANOVA: FOFT (3, 16) = 19.40, p < 0.001, Fig 3B)
Summary
Transient global cerebral ischemia/reperfusion (I/R, restoration of blood flow) injury is a major consequence of cardiac arrest period and resuscitation [1]. Neuronal cells have a high oxygen consumption and metabolic demand, they are very sensitive cell population and are more at risk for ischemic cell death In this regard, drugs acting as free-radical scavengers or inducers of endogenous antioxidant enzymes are suitable candidates for stroke therapy [5, 6]. As rapid removal of glutamate from the extracellular space is crucial for the survival and normal function of neurons, astrocytes are the cell type primarily responsible for glutamate uptake via expressing excitatory amino acid transporters (EAAT) and EAAT2 [11] Among these two, EAAT2 (glutamate transporter 1, GLT-1) is the predominant subtype of glutamate transporters which is located on astrocytes of hippocampus and is responsible to maintain glutamate concentration in brain by 90% of glutamate uptake and attenuate excitotoxic cell death [12, 13]. We investigated the effects of MK-4 administration on oxidative stress, neuroinflammation, cell death and subsequent short- and long-term learning and memory deficits induced by transient global cerebral I/R in vivo
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