Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging

Abstract

Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-D-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26 months) were fed ibuprofen (375 ppm) in NIH31 diet or diet alone for 6 weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2′ cassettes in the hippocampus. GluN1-3 splice form mRNA and C2′ cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation.

Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence

“…In contrast to GluN2A, expression of GluN2B protein [62–64, 67, 68, 78, 83, 84] and GluN2B mRNA [60, 76–78, 83, 85] is generally reported to decline in the hippocampus with advanced age. One problem is that few studies have examined the expression of both subunits in the same animal.…”

Nonsteroidal anti-inflammatory drug, indomethacin improves spatial memory and NMDA receptor function in aged animals

“…Interestingly, non-steroidal anti-inflammatory drugs (NSAIDs) can ameliorate age-related cognitive deficits and impaired NMDA receptor-dependent synaptic plasticity (Casolini, et al, 2002,Jain, et al, 2002,Marquez Loza, et al, 2017,McGuiness, et al, 2017,Melnikova, et al, 2006,Mesches, et al, 2004,Small, et al, 2008). However, whether NSAIDs act on the redox-mediated NMDA receptor hypofunction is unknown.…”

Hydrogen Sulfide Reverses Aging-Associated Amygdalar Synaptic Plasticity and Fear Memory Deficits in Rats

“…Mounting evidence has indicated that aging is associated with hypofunction of NMDARs in regions of the brain associated with synaptic plasticity, memory, and learning ( Kumar, 2015 ). For instance, NMDAR-mediated excitatory postsynaptic potentials (EPSPs) in the hippocampus are decreased in aged rodents ( Yang et al, 2010 ; Haxaire et al, 2012 ) and reduced protein expression of NMDARs is observed in the hippocampus of aged animals ( Liu et al, 2008 ; Zhao et al, 2009 ; Marquez Loza et al, 2017 ). Nowadays, it is generally accepted that hypofunction of NMDARs contributes to impediments in memory and learning that occur with increased age ( Das and Magnusson, 2011 ; Foster, 2012 ; Kumar and Foster, 2013 ; Li et al, 2017 ) and augmenting the expression and functional activity of the NMDAR subunit could overcome the cognitive impairments in aged animals ( Slutsky et al, 2010 ; Robillard et al, 2011 ; Brim et al, 2013 ; Wang et al, 2014 ).…”