Main Research Interest
- Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptive responses that protect the brain against additional stress from the same (tolerance) or other (cross-tolerance) stimuli. Ischemic tolerance (IT) is an endogenous phenomenon which can result in subsequent resistance to severe ischemic injury. This phenomenon has been reported in several organs, including brain. Among different stresses, hypoxia, ischemia, anoxia, oxidative stress, and inhibitors of oxidative phosphorylation induce tolerance to subsequent cerebral (focal or global) ischemia. Most of such stimuli, however, lack potential for clinical translation due to associated toxicity. For this reason, safe non-pharmacological stimuli have been sought. The induction and maintenance of cerebral ischemic tolerance may be mediated through changes in expression availability of a variety of mediators, including NMDA receptors, antiapoptotic factors, interleukin-1, superoxide dismutase, reactive oxygen species, nitric oxide dependent p21 ras activation, metallothioneins, activation of vascular endothelial growth factor receptor and Akt, erythropoietin, caspase-3, NF-κB and proinflammatory cytokines. Meanwhile, tumor necrosis factor -α, (TNF-α) may be an important mediator of ischemic tolerance, and is released in soluble form by the action of a membrane-anchored zinc protease called TNF-α converting enzyme (TACE). In our laboratory, we have recently shown that pretreatment with intermittent or prolonged normobaric hyperoxia (HO) both induce cerebral neuroprotection in rat brain: in particular, intermittent HO reduced brain edema and Evans Blue (EB) extravasations significantly. We have recently shown that pretreatment with intermittent and prolonged HO upregulates glutamate transporters, TACE, serum TNF-α, NF-κB, PKC, metabotropic Glutamate receptors, lipidomics, Na-Ca exchangers, TNF-a receptors, and antioxidant enzymes in the rat brain and confers different degrees of neuroprotection in the rat brain [13].
- Brain ischemia induces the release of excitatory amino acids, with subsequent receptor activation leading to calcium influx, metabolic and electrophysiological dysfunction, and oxidative stress (including lipid peroxidation). Subsequent reperfusion worsens this oxidative stress, potentiating ischemic injury. Diets rich in antioxidants might thus offer neuroprotection in cases of ischemic stroke. The ‘Mediterranean diet’ is powerfully antioxidant, and a number of international scientific organizations now recommend a modified version to prevent conditions in which oxidative stress may play an etiological role. A key component of this diet is olive oil, which contains monounsaturated fatty acids (MUFA) and polyphenols, compounds with a clear antioxidant effect. In our laboratory, we have recently shown that pretreatment with virgin olive oil and olive leaf extract is related to improved blood brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia. Anti-oxidant agents of olive (Oleuropein, Tyrosol and hydroxytyrosol) administration enhance plasma antioxidant capacity and lowering production of pro-inflammatory and prothrombotic mediators in laboratory animals. On the other hand, monounsaturated fatty acids (MUFA) modulate K channels and hyperpolarize resting membrane potential. Therefore, it may be inducing neuroprotection.
By studying the biological mechanisms associated with ischemic preconditioning, we hope to identify completely novel neuroprotective strategies that may be applicable for the management of patients who may be at risk of cerebral ischemia (e.g. insufficient blood supply to the brain during major heart surgery; surgical management of cerebral aneurysms). Initially, these researches are now funded by Iran National Science Foundation (INSF), Shahid Beheshti University, and Razi Herbal Medicine Research Center.