ABSTRACT
Inflammatory processes in the central nervous system are thought to contribute to Alzheimer's disease (AD). Chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of Alzheimer's disease. There are very few studies, however, on the cognitive impact of chronic NSAID administration. The N-methyl-d-aspartate (NMDA) receptor is implicated in learning and memory, and age-related decreases in the NMDA NR2B subunit correlate with memory deficits. Sulindac, an NSAID that is a nonselective cyclooxygenase (COX) inhibitor was chronically administered to aged Fischer 344 rats for 2 months. Sulindac, but not its non-COX active metabolite, attenuated age-related deficits in learning and memory as assessed in the radial arm water maze and contextual fear conditioning tasks. Sulindac treatment also attenuated an age-related decrease in the NR1 and NR2B NMDA receptor subunits and prevented an age-related increase in the pro-inflammatory cytokine, interleukin 1beta (IL-1beta), in the hippocampus. These findings support the inflammation hypothesis of aging and have important implications for potential cognitive enhancing effects of NSAIDs in the elderly.
Subject(s)
Aging/drug effects , Aldehyde Dehydrogenase/genetics , Encephalitis/drug therapy , Memory Disorders/drug therapy , Receptors, N-Methyl-D-Aspartate/drug effects , Sulindac/pharmacology , Aging/metabolism , Aldehyde Dehydrogenase, Mitochondrial , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Encephalitis/physiopathology , Encephalitis/prevention & control , Interleukin-1/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Nootropic Agents/pharmacology , Nootropic Agents/therapeutic use , Rats , Rats, Inbred F344 , Receptors, N-Methyl-D-Aspartate/metabolism , Sulindac/therapeutic use , Treatment Outcome , Up-Regulation/drug effects , Up-Regulation/physiologyABSTRACT
There is evidence that blocking beta-noradrenergic receptors will cause deficits in some forms of learning. We investigated the effects of systemic injections of 1, 5, and 10 mg/kg doses of propranolol on acquisition of delay eyeblink conditioning in 3-month-old Fischer 344 rats. We presented a 3-kHz, 90-dB tone as a conditioning stimulus and a 6 psi airpuff as our unconditioned stimulus to freely moving rats. We monitored eyelid activity using EMG signals. The treatment subjects were injected with either propranolol or saline 0.5 h prior to daily training sessions. Two groups of control subjects, one receiving injections of saline and one receiving injections of 5 mg/kg propranolol, received daily training sessions with unpaired and randomized presentation of the tone and airpuff. Each daily training session for the treatment groups consisted of 27 paired training trials and 3 conditioned stimulus-alone training trials. Rats injected with saline vehicle or with 1 mg/kg propranolol achieved a 60% or better learned response rate within two training sessions. Rats injected with 5 or 10 mg/kg propranolol never achieved a response rate significantly different from animals that received unpaired, random presentations of the tone and airpuff stimuli. These results agree with prior studies from our lab that have shown a dose-dependent effect of beta-noradrenergic receptor blockade on learning in rabbit eyeblink conditioning as well as in a runway, motor learning paradigm. We believe that the beta-noradrenergic system plays an important role in learning and memory in more than one cerebellar-dependent learning paradigm.
