Nefiracetam improves Morris water maze performance following traumatic brain injury in rats (original) (raw)
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Brain Research, 2009
Hypertonic saline (HTS) is an accepted treatment for traumatic brain injury (TBI). However, the behavioral and cognitive consequences following HTS administration have not thoroughly been examined. Recent preclinical evidence has suggested that nicotinamide (NAM) is beneficial for recovery of function following TBI. The current study compared the behavioral and cognitive consequences of HTS and NAM as competitive therapeutic agents for the treatment of TBI. Following controlled cortical impact (CCI), bolus administrations of NAM (500 mg/kg), 7.5% HTS, or 0.9% saline Vehicle (1.0 mL/kg) were given at 2, 24, and 48 h post-CCI. Behavioral results revealed that animals treated with NAM and HTS showed significant improvements in beam walk and locomotor placing compared to the Vehicle group. The Morris water maze (MWM) retrograde amnesia test was conducted on day 12 post-CCI and showed that all groups had significant retention of memory compared to injured, Vehicle-treated animals. Working memory was also assessed on days 8-20 using the MWM. The NAM and Vehicle groups quickly acquired the task; however, HTS animals showed no acquisition of this task. Histological examinations revealed that the HTS-treated animals lost significantly more cortical tissue than either the NAM or Vehicle-treated animals. HTS-treated animals showed a greater loss of hippocampal tissue compared to the other groups. In general, NAM showed a faster rate of recovery than HTS without this associated tissue loss. The results of this study reiterate the strengths of NAM following injury and show concerns with bolus administrations of HTS due to the differential effects on cognitive performance and apparent tissue loss.
Restorative neurology and neuroscience, 2006
As deficits in memory and cognition are commonly observed in survivors of traumatic brain injury (TBI), causing reduced quality of life for the patient, a major goal in experimental TBI research is to identify and evaluate cognitive dysfunction. The present study assessed the applicability of the serial Morris water maze (MWM) test to determine cognitive function following experimental TBI in the same group of rats which is particularly important for long-term studies and increasingly valuable for the evaluation of novel treatment strategies. Male Sprague-Dawley rats (n = 27) were anesthetized and subjected to either sham injury (n = 9) or lateral fluid percussion (FP) brain injury of moderate severity (n = 18). At 4 weeks post-injury, animals were trained in a water maze over 3 days (acquisition/learning phase) to find a submerged platform. At 8 weeks post-injury the hidden platform was then moved to the opposite quadrant, and animals were trained to find the new position of the pl...
Effects of nefiracetam on amnesia animal models with neuronal dysfunctions
Behavioural Brain Research, 1997
The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl) acetamide (nefiracetam; DM-9384), on learning and memory in several amnesia animal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiazepoxide-and cycloheximide-induced amnesia. Anti-amnesic action of nefiracetam on scopolamine model was antagonized by nifedipine and flunarizine, but not by diltiazem. Repeated administration of nefiracetam to AF64Atreated animals improved impairment of learning and memory as well as the alterations in cholinergic and monoaminergic neurotransmitters in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning accompanied by a marked reduction in choline acetyltransferase (CHAT) and acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxideinduced delayed and acute amnesia. Nefiracetam stimulated acetylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, 7-aminobutyric acid (GABA) turnover and glutamic acid decarboxylase activity, and facilitated the Na+-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca 2÷ channel. The dose-response curves of nefiracetam were bell-shaped in both behavioral and biochemical studies. Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca 2÷ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia.
Journal of Neurotrauma, 2011
Previous studies have demonstrated that the compound N-acetyl-L-tryptophan (NAT) reduces brain edema and improves functional outcome following traumatic brain injury (TBI). In this study we examined whether this effect was mediated via the neurokinin-1 receptor, and whether there was an effect on axonal injury. We also explored whether the compound was effective, even when administered at delayed time points. Male Sprague-Dawley rats were subject to acceleration-induced, diffuse TBI and administered NAT, its inactive D-enantiomer, or saline vehicle. In contrast to NAT (2.5 mg/kg), the inactive D-enantiomer was ineffective at improving rotarod motor performance after TBI. NAT also improved cognitive outcome as assessed by the Morris water maze and novel object recognition tests, and reduced axonal injury at 5 and 24 h after TBI as assessed by amyloid precursor protein immunohistochemistry. However, efficacy of the membrane-impermeable NAT was limited to administration within 5 h, whereas administration of a form of NAT, L-732,138 (47 mg/kg), in which a trifluoromethyl benzyl ester group has been added, making it highly lipid soluble and able to cross the intact blood-brain barrier, significantly improved motor outcome, even when administration was delayed by as much as 12 h. We conclude that the neuroprotective effects of NAT are receptor-mediated, and that administration of the membrane-permeable form of the compound can be effective even up to 12 h after TBI.
The nootropic compound BMY-21502 improves spatial learning ability in brain injured rats
Brain Research, 1993
Although long-lasting cognitive dysfunction often follows clinical traumatic brain injury (TBI), few pharmacologic regimens have been developed to treat post-traumatic cognitive deficits. We have previously shown that, in the rat, experimental lateral fluid-percussion (FP) brain injury induces a profound impairment in retrograde memory. In the present study, we characterized alterations in the ability of rats to learn a novel task following lateral FP brain injury and examined the potential modulatory effects of the nootropic cognitive enhancer BMY-21502 on post-injury learning. Male Sprague-Dawley rats were subjected to lateral (parasagittal) FP brain injury of moderate severity (2.4 atm) or sham surgery (no injury). On days 7 and 8 post-injury, animals were tested in a Morris water maze for their ability to learn to navigate to a submerged, invisible platform using external visual cues. BMY-21502 (10 mg/kg) or vehicle was administered 30 min prior to the first trial on both days. A highly significant (P < 0.001) impairment in post-injury learning was observed in vehicle-treated brain-injured animals compared with vehicletreated sham animals. Injured animals treated with BMY-21502 at one week post-injury showed significant (P < 0.05) improvement in post-injury learning ability compared to injured animals treated with vehicle. Paradoxically, in uninjured control animals BMY-21502 treatment appeared to worsen learning scores. The results of this study indicate that BMY-21502 may be useful for attenuating the dysfunction in learning ability that occurs following TBI.
Experimental Neurology, 2000
Although several noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to be substantially efficacious in experimental models of brain trauma, side effects associated with this class of compounds have impeded clinical application. Therefore, new noncompetitive NMDA receptor antagonists have been developed, including NPS 1506, that appear to be nontoxic but retain efficacy. In the present study, we evaluated the efficacy of NPS 1506 in a model of parasagittal fluid percussion brain trauma in the anesthetized rat. Administration of 1 mg/kg NPS 1506 at both 10 min and 4 h posttrauma induced no changes in brain temperature, mean arterial pressure, pulse, or arterial blood gasses. At 1 week postinjury, animals treated with the same dosing regimen of NPS 1506 demonstrated a dramatic attenuation of memory dysfunction evaluated by a water maze task (P < 0.02) and had greatly reduced neuron death in the CA3 subfield of the hippocampus (P < 0.01). However, NPS 1506 treatment did not significantly affect the extent of cortical tissue loss following injury. Since memory dysfunction and hippocampal damage are common and potentially related consequences of brain trauma in humans, our results suggest that NPS 1506 treatment may have clinical utility.
Conceptual and Practical Issues in the Pharmacological Treatment of Brain Injury
Journal of Neural Transplantation and Plasticity, 1993
It is only within the last ten years that research on treatment for central nervous system (CNS) recovery after injury has become more focused on the complexities involved in promoting recovery from brain injury when the CNS is viewed as an integrated and dynamic system. There have been major advances in research in recovery over the last decade, including new information on the mechanics and genetics of metabolism and chemical activity, the definition of excitotoxic effects and the discovery that the brain itself secretes complex proteins, peptides and hormones which are capable of directly stimulating the repair of damaged neurons or blocking some of the degenerative processes caused by the injury cascade. Many of these agents, plus other nontoxic naturally occurring substances, are being tested as treatment for brain injury. Further work is needed to determine appropriate combinations of treatments and optimum times of administration with respect to the time course of the CNS disorder. In order to understand the mechanisms that mediate traumatic brain injury and repair, there must be a merging of findings from neurochemical studies with data from intensive behavioral testing.
Behavioural Brain Research, 1997
We characterized alterations in the ability of concussive brain injury (CBI) models to perform a water-finding task and examined effects of (+)-eburnamenine-14-carboxylic acid (2-nitroxyethyl) ester (VA-045), a novel apovincaminic acid derivative, on posttraumatic impairments in latent learning and memory processes. Two types of CBI-induced amnesia (retrograde and anterograde) were produced by means of post-or preacquisition head impact using a simple weight-drop device. Profound impairments of latent learning and memory processes related to retention and retrieval were observed in the CBI mice. In the CBI-induced retrograde amnesia model, VA-045 (0.5-4.0 mg/kg) significantly ameliorated impairments of latent learning and retention in both the retention test and the retest. In the CBI-induced anterograde amnesia model, the protective effects of the compound on impairments in latent learning and retention or retrieval were significant in both the retention test and the retest. These results suggested that VA-045 may be a novel cognitive enhancer for attenuating or protecting against the learning and memory dysfunction associated with CBI.
Brain Research, 1995
Mild to moderate traumatic brain injury (TBI) is associated with enduring impairments of cognitive function in both humans and animals. However, few experiments have investigated the role of post-injury pharmacologic strategies for attenuating the observed cognitive impairment after TBI. This investigation examined the effects of selective blockade of the presynaptic muscarinic M2 autoreceptor with BIBN 99 on cognitive recovery following rodent TBI. Experiment 1 investigated the effects of delayed post-injury administration of BIBN 99 on cognitive performance following moderate central fluid percussion TBI (2.1 + 0.05 arm). On days 11-15 after injury-cognitive performance was assessed with a Morris water maze (MWM) task. One hour before MWM testing injured rats were injected (s.c.) with either vehicle (n = 9), 0.5 (n = 8), or 1.0 (n = 8) mg/kg of BIBN 99. Results indicated that injured rats receiving the delayed post-injury treatment with BIBN 99 performed no better than injured-vehicle treated rats. In experiment 2, injured rats were injected (s.c.) once daily with either vehicle (n = 9), 0.5 (n = 9), or 1.0 (n = 9) mg/kg of BIBN 99 throughout the duration of the experiment beginning 24 h after TBI. Sham-injured animals injected (s.c.) with vehicle (n = 9) or 1.0 (n = 8) mg/kg of BIBN 99 were included for comparison. On days 11-15 after injury, cognitive performance was assessed with the MWM procedure. Results of the second experiment indicated that both doses of BIBN 99 were effective in attenuating cognitive deficits in the MWM as compared to the injured-vehicle treated animals (P < 0.05 for both comparisons). The results also revealed that sham-injured animals were unaffected by the 1.0 mg/kg dose of BIBN 99 on MWM performance. Thus, cholinergic enhancement by selective blockade of the presynaptic M, autoreceptor is an efficacious strategy for the post-injury amelioration of cognitive deficits following experimental TBI. However, time and duration of administration may be important factors that affect the efficacy of treatment.
Haloperidol, but Not Olanzapine, Impairs Cognitive Performance After Traumatic Brain Injury in Rats
American Journal of Physical Medicine & Rehabilitation, 2003
Wilson MS, Gibson CJ, Hamm RJ: Haloperidol, but not olanzapine, impairs cognitive performance after traumatic brain injury in rats. Am J Phys Med Rehabil 2003;82:871-879. Objective: Traumatic brain injury can cause a variety of impairments, including persistent alterations in personality, mood, and cognition. Antipsychotic agents are frequently used to treat pathologic behaviors in traumatic brain injury patients, but the influence of prolonged administration of such drugs on cognition after injury is unknown. The effects of two antipsychotic drugs on cognitive recovery after traumatic brain injury were assessed using the fluid percussion model in rats.