YAN XU, DEQIN GENG
Affiliated Hospital of Xuzhou Medical College Department of Neurology, Xuzhou Jiangsu, 221003, People Republic of China.
Abstract: N-methyl-D-aspartate (NMDA) receptor is a specific type of inotropic glutamate receptors (iGLuRs) located in the central nervous system which functioned in mediating synaptic plasticity under physiological and pathological conditions in the state of 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 reports, NMDA receptor contains N-methyl-D-aspartate receptor subtype 2B (NR2B) involved in stimulating neural excitotoxicity, while the N-methyl-D-aspartate receptor subtype 2B (NR2A) functioned as neuroprotection. Therefore, combination of highly specific agonists for NR2A and specific antagonists for NR2B may have a new direction for the treatment of the ischemic stroke.
Keywords: NMDA receptor, ischemic stroke, NR2B, NR2A, neuron protection, neural excitotoxicity
Citation: Yan X, Dexin G. The research of NMDA receptor and ischemic stroke. J Gen Neurol 2016; 1(1): x-x.
*Correspondence to:
Received: Accepted: Published Online:
Introduction
Cerebral ischemia able to induce 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.
Overview of NMDA receptor
NMDA receptors, kainite receptor (KAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) belong to ionotropic glutamate receptors (iGLuRs). Furthermore, there is a class of metabotropic glutamate receptors (mGLuRs) in the central nervous system by G-protein coupled receptors, regulating intracellular synthesis through second messengers systems. The main role of NMDA receptors by high calcium permeability mediated excitatory synaptic plasticity toxic effects under pathophysiological state, play an essential role in maintaining the physiological function of the central nervous system effect.
NMDA receptor molecular configuration
NMDA receptor is complex heterotetramer with ion channel that composed by NR1, NR2 and NR3 subunits in three different 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].
Distribution of NMDA receptor l
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].
Physiology and pathological effects of NMDA receptor
The function of NMDA receptors is to mediate excitatory amino acid neurotransmitter 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, but also in long-term potentiation (long-term potentiation, LTP) and long-term depression (long-term depression, LTD) and other neurological activity. NMDA receptor also participate in the more advanced brain functions activities such as learning and memory as well as some other acts
[6]. NMDA receptor 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 involved in the 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 function in the nervous ischemic stroke during hypoxia ischemia.
Role of NMDA receptor in ischemic cerebral apoplexy
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 profound understanding to NMDA receptors which are involved in the signaling pathway of excitotoxic effects. NMDA receptors can induce apoptosis by activating glycogen synthase kinase 3β (GSK3β); and neuronal nitric oxide synthase (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 able to 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. This results in excessive activation of post-synaptic NMDA receptors. The excess of Ca
2+ influx can lead to intracellular free Ca
2+ 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 that lead to the permeability of mitochondrial membranes produce changes that caused 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 aggravate neuronal injury. The act of glutamate on ischemia caused by NMDA receptors will decreased 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. Inflammatory response able to 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].
The role of NMDA receptor in the nerve protection in the process of cerebral ischemia
Gould
[16] has found that within one week of deactivation NMDA receptor in the rat nervous system in the year of 1994 results in decrease in the number of healthy hippocampal neurons in rats, and this report has been confirmed to be the earliest related to NMDA receptor. Additional reports suggested that the NMDA receptor that blocked the initial development may intensify brain damage caused by ischemia and hypoxia, and leading to widespread apoptosis
[17]. Besides that, certain reports explained that if the hypoxic-ischemic brain after the injury and blocking the activity of the NMDA receptor that results in survived neurons stimulate to accelerate apoptosis
[18].
NMDA receptors that involved in the neuroprotection related to mutiple signaling pathway (PI3K/Akt signaling pathway, ERK signaling pathway, before Ca
2+/ Calmodulin dependent kinase survival signaling pathway, CREB pathway and NF-kB pathway). PI3K/Akt signaling pathway neuronal protection mechanisms
[19]: the 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; catalyze the phosphorylation of FOXO transcription factors, and lowered its expression as well as affected the downstream apoptotic gene expression; phosphorylation of apoptotic gene Bcl-2 family member BAD which can inhibit pro-survival Bcl2/blocking action of Bcl-XL; 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 regarded as the prime reason for ischemic tolerance and mechanism of ischemic preconditioning, which played a long-lasting anti-apoptotic role in treatment of cerebral ischemia
[20,24].
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 and that is NMDA receptors not only participate in the nerve injury, but also participate in the neuroprotective effect, and biological role NMDA receptor is in line with the bell-shaped curve theory
[25]: Under certain circumstances excitatory neurons stimulated neurons is positively correlated. This explained the increased of stimulation has gradually increased neuronal response. At the point peak of, it turns to negatively correlated that showed excessive stimulation will lead to enhanced neuronal responses weakened. Alternatively, 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 concludes that the structures of NMDA receptors which lies in and out of synapse is different, and it also play contrary effect 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]. There are certain research currently supports that 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. The neuroprotective effect mainly by 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].
The treatment of the cerebral ischemia and NMDA receptor
There are two main aspects in treatment of the ischemic stroke. Firstly, is to restore cerebral perfusion and improve blood supply to ischemic brain tissue and is called thrombolytic therapy. Secondly, 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 applications 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.
The new inspiration of the NMDA receptor in the treatment of cerebral ischemia
Research had shown that NMDA receptors in the treatment of ischemic stroke played a mediated excitotoxicity role as well as a mediates neuroprotection role. Currently, studies has shown the understanding of the structure and the role of NMDA receptors in the process of cerebral ischemia and the knowledge of cerebral ischemia NMDA receptor-mediated signaling pathways and various ischemia and reperfusion in NMDA receptors. This studies will be very useful in the treatment of ischemic stroke. NMDA receptor antagonists currently is not ideal, further research on the NMDA receptor subunits in need to contribute to the development of specific NMDA receptor subtype antagonists. NR2B selective antagonists and NR2A agonists in combination also provides a direction for the treatment of ischemic stroke that may compensate for the lack of thrombolytic therapy applied to a certain extent. In addition, clarify cerebral ischemia on glial cells NMDA receptors may also give researchers the treatment of ischemic stroke with new inspiration.
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