A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats
Introduction
Neuroinflammation is a complex process of the cells within CNS including neurons and microglia with elevated levels of proinflammatory cytokines. The NMDA receptor (NMDAR) is involved in cellular mechanism for learning and memory function. Neuroinflammation with overexpression of cytokines is a characteristic of the brain pathology present in Alzheimer's disease (AD) (Mrak and Griffin, 2005). Animal studies have suggested the involvement of astrocytic glutamate receptor in glial cell signaling (Schipke et al., 2001, Wong, 2006). Activated microglia produces a variety of proinflammatory and neurotoxic factors, including cytokines, such as tumor necrosis factor (TNF-α); interleukin-1β (IL-1β); and free radicals, such as nitric oxide (NO) and superoxide (Banati et al., 1993, Minghetti and Levi, 1998). NO is also produced by activated astrocytes and has also become one of the major contributors in the formation of reactive nitrogen species. Reactive oxygen species (ROS) and NO which have been overexpressed during the neuroinflammatory process, are able to directly influence the induction of long term potentiation (LTP) (Min et al., 2009). Min et al. (2009) also suggested that proinflammatory cytokines and other molecules that are overexpressed during the neuroinflammatory process influence neurotransmitter release, receptor signal transduction mechanism and finally, the ability of the synapses to undergo long-term potentiation (LTP). NMDA receptors (NMDARs) are of major interest because they are involved in synaptogenesis, neuronal circuitry formation, synaptic plasticity, learning and memory, as well as in the molecular pathogenesis of neurological disorders (During et al., 2000).
NR2A and NR2B are likely to play a major role in synaptic plasticity modulating LTP and long-term depression (LTD) respectively (Monyer et al., 1994). Overactivity of glutamatergic NMDARs results in excitotoxicity which may participate in microglial activation in the hippocampus of brain (Chang et al., 2008). The triggering of LTP requires synaptic activation of post-synaptic Ca2 + entry and NMDARs. Proinflammatory cytokines crucially influence several key molecular steps that are considered to be essential in the induction of NMDARs (Tan et al., 2007). Proinflammatory cytokines also dose dependently enhance NMDARs mediated currents and NMDA-induced intracellular Ca2 + increase (Yoshiyama and Groat, 2007). Tweedie et al. (2007) reported that proinflammatory cytokines are involved in NMDAR activity in astrocytes. Further, Massey et al. (2004) had suggested that NR2A containing NMDARs are required for LTP whereas NR2B containing NMDARs are required for LTD in memory.
Memantine is an uncompetitive NMDAR antagonist and its mechanism of action is neuroprotective and potentially therapeutic in several neuropsychiatric diseases. Memantine can improve cognition and neuronal plasticity under pathological conditions might seem to be paradoxical (During et al., 2000). Ibuprofen is the most commonly used and most frequently prescribed NSAID (Bradbury, 2004). Its effects are due to the inhibitory actions on cyclooxygenases (COX), which are involved in the synthesis of prostaglandins and have an important role in the production of inflammation. Proinflammatory cytokines are thought to have a pivotal role during the physiological crosstalk occurring between neurons and astrocytes and the cytokine mediated modulation of glia–neuron communication (Tarkowski et al., 2003). It has been reported that intracerebroventricular (ICV) injection of STZ causes spatial memory impairment by disrupting glucose utilization through an insulin-dependent mechanism and neurotoxicity in myelin in the cerebral cortex and hippocampus (Shoham et al., 2003).
However, the effect of STZ (ICV) causing memory impairment on neuroinflammation and NMDA receptor subunits has not been explored. In this study we describe the alteration of the NMDAR subunits and involvement of neuroinflammation in STZ (ICV) induced memory impaired rats.
Section snippets
Animals
Adult male Sprague Dawley (SD) rats weighing 230–250 g were used in this study. They were kept in polyacrylic cages in a group of 5 and maintained under standard housing conditions (room temperature 25 ± 1 °C and humidity 60–65%) with 12 h light and dark cycle. Food and water were available ad libitum but food removed during experimental period from 1 h prior to administration of drug till completion of the trials (approximate 2–3 h). The animals were procured from the Laboratory Animal Division of
Effect of Memantine and Ibuprofen on STZ induced memory impairment in rat
The memory function was assessed on days 14, 15 and 16 after STZ injection in the Morris water maze test. In aCSF group escape latency time (ELT) in the 2nd and 3rd sessions was significantly lower than the 1st session [aCSF group: F (2, 12) = 10.13]. There was no significant change in latency to reach the platform in STZ treated rats in 2nd and 3rd sessions as compared to the 1st session [F (2, 12) = 1.78, P > 0.05]. Treatment with Memantine (10 mg/kg per day) [F (2, 12) = 4.33, P < 0.005] and Ibuprofen
Discussion
Streptozotocin (STZ) ICV is a well established memory impairment model in rodents and known to cause oxidative stress in rats (Agrawal et al., 2009). In the present study, we have also found that STZ caused memory impairment in rat which was prevented by pretreatment with clinically used anti-dementic drug, Memantine and anti-inflammatory drug Ibuprofen. Inflammatory processes within the CNS lead to increased production of proinflammatory cytokines that increase the formation of reactive oxygen
Conclusion
The current study suggests that neuroinflammation induced by STZ (ICV) is associated with impaired NMDA receptor function and may also contribute to the memory impairment in rats.
Acknowledgments
Financial support to Shivika Rai from CSIR-New Delhi is gratefully acknowledged.
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