The research of NMDA receptor  and ischemic stroke
 
YAN XU   DEQIN GENG
(Affiliated Hospital of Xuzhou Medical College Department of Neurology XUZHOU JIANGSU 221003)
       Abstract: N- methyl -D- aspartate receptor is a kind of iGLuRs lies in the central nervous system  which fuctioned in mediating synaptic plasticity under physiological and pathological conditions of state excitotoxic effects. NMDA receptor has the dual role in nerve damage and nerve protect in the process of ischemic stroke. According to the current research, NMDA receptor contains NR2B subtype which worked in  stimulating neural excitotoxicity, while the NR2B receptor subtybe functioned in the protcetion of the nerve unit. Thus, combined NR2B selective antagonists  with NR2B selective agonists can offer a new direction for the treatment of the ischemic stroke.
 Key Words: NMDA receptor ,ischemic stroke,NR2B, NR2A, Neuron protection,Neural excitotoxicity
 
Cerebral ischemia can give rise to a series of pathophysiological changes, including changes in hemodynamics, biochemistry and neurobiology. NMDA receptors play an important role in the pathophysiology of cerebral ischemia as well as a series of events in reperfusion injury caused.
 
1.The overview of NMDA receptor
  NMDA receptors and KAR, AMPAR belong to ionotropic glutamate receptors (iGLuRs), in addition, there is a class of metabotropic glutamate receptors (mGLuRs) in the central nervous decency by G- protein coupled membrane , regulating intracellular second messengers play a role. The main role of NMDA receptors by height of calcium permeability mediated excitatory synaptic plasticity toxic effects and pathological state under physiological state, play an essential in maintaining the physiological function of the central nervous system effect.
 
1.1  NMDA receptor molecular configuration
  NMDA receptor is complex heterotetramerican with ion channel which was composed by NR1, NR2 and NR3 subunits three in various combinations polymerization.  As for the function of the NMDA receptor ion channel complex, NR1 subunit is an integral component played on the basis of ion channel function; and NR2 subunits of NMDA receptors is determined conductive composite ion channels, dynamics and drug sensitivity regulatory subunits [1]. NR2 or NR3 alone is inactive, only the NR1 NMDA receptor complex binding to  exhibit the appropriate activity. When NMDA receptors need to combine the two amino acids glutamate and glycine to activate, and glycine and glutamic acid in combination with different subunits, respectively, located NR2 glutamate binding subunit binding site, glycine binding site can be found in NR1 or NR3 subunits [2].
 
1.2  distribution of  NMDA receptor
NMDA receptors are widely distributed in various parts of the central nervous system which can be presented in neuronal dendrites, also be presented in neurons [3], both within the postsynaptic receptors also exist outside synaptic receptors [4] ,  in the cerebral cortex, striatum, hippocampus, amygdala highest density [3]. Furthermore, in addition  neurons, such as the oligodendrocytes were also can be found NMDA receptor in glial cells[5].
1.3  physiology and pathological effects of NMDA receptor
The function of NMDA receptors is to mediate excitatory amino acid neurotransmitter transport which playing a very important role in maintaining the normal function of the central nervous system, not only in mediating synaptic plasticity and excitability transfer plays an essential role, but also in long-term potentiation (long-term potentiation, LTP) and long-term depression (long-term depression, LTD) and other neurological activity , and NMDA receptor also participate in the more advanced brain functions Activities such as learning and memory as well as some other acts [6]. NMDAR activation is essential for neuronal survival, under physiological conditions, NMDA receptor will have a certain degree of activation, mediates a role in protecting neurons can regulate neuronal growth, differentiation, migration and survival, regulating dendritic, axonal growth, affect the formation of synapses and neuronal circuits [7]; and in some pathological conditions, activation of NMDA receptors also have a neuroprotective effect [8]. NMDA receptors get involved in neural development, synaptic plasticity, learning and memory and cognitive and other neurological regulation as well as in the pathological process of schizophrenia and epilepsy and neurodegenerative diseases [9], not appropriate NMDA receptor activation is associated with a variety of neurological diseases, such as in the development of neural , NMDA receptor activity may be associated with inadequate schizophrenia, and NMDA receptor function may be associated with epilepsy is hyperactive [10]; NMDA receptor excessive activation will lead to a reduction in certain brain hypoxic injury and chronic neurodegeneration neurons [11]. This article take focuses on NMDA receptors’founction in the nervous ischemic stroke during hypoxia ischemia .
2.the role of NMDA receptor in ischemic cerebral apoplexy
2.1 the role of NMDA receptor in the nerve damage in the process of cerebral ischemia
       The  "excitatory neurons toxicity hypothesis" of ischemic brain injury has been put forward  in the 1980s. At present, the researchers have been already have a profund understanding to NMDA receptors  which are involved in the signaling pathway of excitotoxic effects . NMDA receptors can induce apoptosis by activating GsK3B;and  nNOs pathway activation can also lead to neuronal apoptosis or death; and the excessive activation of NMDA receptors can also make calpain activation which  resulting in mGluRl decomposition and reduce protein kinase B (PKB ) activity , this process can  accelerate the release of apoptotic factors to promote apoptosis [9]. There are many factors that  affect NMDA receptors, such as ion effect, oxidative stress, cytokines, inflammatory reactions. and massive release of glutamate in the process of Cerebral ischemia,  because of the glutamate neurons was in a high level  environment, which resulting in excessive activation of post-synaptic NMDA receptors. The excess of Ca2 + influx can lead to intracellular free Ca2 + increases which can work in the formation of calcium overload and activation of proteases and endonucleases and lipase, promote production of nitric oxide and free radicals, so that the permeability of mitochondrial membranes produce changes which can lead to neuronal damage or death [12]. The role of NO as well as retrograde messenger may promote presynaptic glutamate release [13], increase activation of NMDA glutamate receptors, and form a vicious cycle which can aggravat neuronal injury. after glutamate act on  ischemia caused by NMDA receptors, this process  decreasing the PKB of IGF-1 receptor and phosphorylation,  and weakening downstream IGF-1 signaling pathway, as well as weakening its protective effect on nerve cells [14]. It will produce numerous cytokines to regulate stimulate cerebral ischemia, weaken or enhance inflammatory responses and injuries, such as IL-1, IL. 6, INFY, BDNF, GF, GDNF and so on. Inflammatory response can change the form and extent of ischemic neuronal injury, lectin B4-positive inflammatory cells and inflammatory cells release IL-1 B by promoting neuronal NMDA receptor-mediated excitotoxicity, increased ischemia brain damage [15].
 
2.2 the role of NMDA receptor in the nerve protection in the process of cerebral ischemia
   Gould [16] has found that within one week of make-week-old NMDA receptor  can inactivate the rat nervous system in the year of 1994,  and this findings will reduce the number of healthy hippocampal neurons in rats, and this report has been comfirmed to be the earliest  related to NMDA receptor. And the another reports suggestion that the NMDA receptor which blocking the the initial development can worsen brain damage caused by ischemia and hypoxia , and leading to widespread apoptosis [17]; in addition there are reports that if the hypoxic-ischemic brain after the injury blocking the activity of the NMDA receptor, the surviving neurons appears to accelerate apoptosis [18].
      NMDA receptors get involved in the protection of neuronal may related to mutiple signaling pathway (PI3K / Akt signaling pathway,ERK signaling pathway, before Ca2 + / Calmodulin dependent kinase survival signaling pathway, CREB pathway and NF-kB pathway).PI3K / Akt signaling pathway neuronal protection mechanisms [19]: ①the inhibition of glycogen synthase kinase 3β (GSK-3β) activity have an  impact on its downstream substrate NF-kB, c-Jun transcripts, etc., thereby inhibiting the nerve neuronal cell apoptosis; ② catalyze the phosphorylation of FOXO transcription factors, and lowered its expression as well as affected the downstream apoptotic gene expression; ③ phosphorylation of apoptotic gene Bcl-2 family member BAD which can inhibit pro-survival Bcl2 / blocking action of Bcl-XL; ④ promote CREB phosphorylation play regulatory role in cell survival [20]. Thus, PI3K / Akt signal transduction pathway can reduce cerebral ischemia-reperfusion injury [21]. The application of PI3K antagonists can inhibit the activation of Akt1, and nerve damage increased; the application  of PI3K agonists in reperfusion can significantly enhance the phosphorylation of Akt1 to reduce nerve damage as well as infarct size [22]. TLR2 activation  PI3K / Akt signaling pathway in order to promote Akt and GSK-3β phosphorylation as well as reduce ischemia-reperfusion injury [23].  The Phosphorylation of CREB and Regulation of  the downstream gene transcription are regarsed as the main reason for  ischemic tolerance and mechanism of ischemic preconditioning, which played a  long-lasting anti-apoptotic  role in treatment of cerebral ischemia [20,24].
2.3 the overall effect of the NMDA receptor in the process of cerebral ischemia.
In the process of hypoxic-ischemic brain injury, NMDA receptor has the dual function to neurons , that is to say, NMDA receptors not only participate in the nerve injury, but also participate in the neuroprotective effect,and  NMDA receptor biological Learn role  is in line with the bell-shaped curve theory [25]: Under certain circumstances excitatory neurons  stimulated neurons which is positively correlated, i.e. stimulation gradually increased neuronal response has gradually increased, and when reached a peak which will presented  negatively correlated,  that means excessive stimulation will lead to enhanced neuronal responses weakened. In other words, moderate activation of the NMDA receptor can increase the survival rate of neurons, play a neuroprotective effect and promote survival of neurons in action, and excessive and inadequate NMDA receptor activation may cause damage to nerve function, and induces neuronal apoptosis or death [26].
Research suggestion that  the structures of NMDA receptors which lies in and out of synapse is different, and it also play contrary effect in  in the different signaling pathways :  in the synaptic ,NMDA receptor activation to promote neuronal survival and neuroprotective role, while extrasynaptic NMDA receptor activation is leading to nerve cell death [27]. Considerable research is currently supported NR2B-containing NMDA receptors involved in the neural excitotoxicity, and NR2A containing receptor subtypes are involved in the neuroprotective effects [28]. Extrasynaptic and synaptic NMDA receptor agonists damage and adverse effect on pro-survival of neurons explains the NMDA receptor blocker or excitement can aggravate neuronal injury phenomenon. Excitability toxicity mainly by extrasynaptic NR2B-containing NMDA receptor-mediated, thus selectively inhibiting NMDA receptors outside the synapse (or NR2B subunit) will be more therapeutic significance, while neuroprotective effect mainly by the sudden When the touch NR2A subunit containing NMDA receptor-mediated, selective NMDA receptor activation (or NR2A subunit) within synapses also reduce ischemic brain damage an idea, so the treatment of ischemic stroke may be selective bidirectional drug strategy, while using selective NR2B antagonist and agonist NR2A [7].
3. The treatment of the cerebral ischemia and NMDA receptor.
    There are two main aspects in treatment of the ischemic stroke , one is to restore cerebral perfusion and improve blood supply to ischemic brain tissue, this one is thrombolytic therapy; and the other one is the interrupt cerebral ischemic injury cascade, preventing neuronal damage neurons and protection survival [29]. After take rt-PA thrombolytic therapy more than 30% of patients turn for the better, but thrombolysis must be taken within 4.5 hours after stroke , due to the limitation of time windows and contraindications, only 5% of patients may access to  thrombolytic therapy. Reperfusion of blood flow may result in ischemia-reperfusion injury in brain tissue, increasing the original irreversible brain damage and even converted to irreversible damage, eventually leading to neuronal apoptosis. Therefore,  as for the patients with ischemic stroke , it is necessary to restore ischemic tissue blood perfusion as soon as possible , as well as prevent ischemia-reperfusion injury, both to enhance the neuroprotective effect of NMDA receptors, the need of to block the NMDA receptor to nerve injury. Clinical application of NMDA receptor blockers have great side effects,  but to promote the current combination therapy to reduce the side effects of drugs and enhance their neuroprotective effect is advocated. Moreover, NR2B selective antagonists and NR2A selective agonist combined with treatment options will be very promising in the future..
4. The  new inspiration of the NMDA receptor in the treatment of cerebral ischemia.
Research at home and abroad has shown that NMDA receptors in the treatment of ischemic stroke not only played a mediated excitotoxicity role, but also played a mediates neuroprotection role. There is a certain understanding for currently researchers to the role of NMDA receptors in the process of cerebral ischemia have some knowledge of cerebral ischemia NMDA receptor-mediated signaling pathways and various ischemia and reperfusion in NMDA receptors ,  this will the very usefull in the treatment of ischemic stroke . NMDA receptor antagonists currently is not ideal, it still need a further research on the NMDA receptor subunits , and we trust it will contribute to the development of specific NMDA receptor subtype antagonists. NR2B selective antagonists and agonists in combination with selective NR2A also provides a direction for the treatment of ischemic stroke, wich  may compensate for the lack of thrombolytic therapy applied to a certain extent. Also, clarify cerebral ischemia on glial cells NMDA receptors may also give researchers the treatment of ischemic stroke with new inspiration.