[A 43-year-old patient with character changes, recurrent impaired consciousness and retrograde amnesia]. / 43-jähriger Patient mit Wesensveränderung, rezidivierenden Bewusstseinsstörungen und retrograder Amnesie.

A 43-year-old male patient with recurring impaired consciousness and retrograde amnesia was admitted to the department of neurology. During the neurological evaluation no pathological findings could initially be revealed but one day the patient was confused again and presented with inadequate behavior: at this time a blood glucose value of 40 mg/dl was measured. For further evaluation the patient was transferred to our department. As the reason for the impaired consciousness was suspected to be of neuroglucopenic origin a rapid adrenocorticotropic hormone (ACTH) stimulation test was first performed to rule out adrenal insufficiency. For further evaluation a fasting test was conducted: after 48 h an episode with neuroglucopenic symptoms occurred again which disappeared after intravenous administration of glucose. The laboratory results of glucose, insulin and c-peptide determined at this point in time led to the diagnosis of an insulinoma. By ultrasound examination a hypoechogenic lesion 1.5 cm in size could be shown in the head of the pancreas and was confirmed by magnetic resonance imaging (MRI). After duodenum-preserving partial pancreatic head resection with enucleation of the insulinoma no further neuroglucopenic symptoms occurred.

Nootropic activity of Celastrus paniculatus seed.

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050 mg/kg) and to mice (500 and 1500 mg/kg). The results were compared to piracetam (100 mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35 mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia.

CONTEXT: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged. OBJECTIVE: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice. MATERIALS AND METHODS: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT(1/2) blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE. RESULTS AND DISCUSSION: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE. CONCLUSION: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.

Retrograde amnesia produced by several treatments: evidence for a common neurobiological mechanism.

This experiment examined the effects on memory of various amnestic treatments in animals earlier treated with the alpha-adrenergic antagonist phenoxybenzamine (PBZ). Thirty minutes before being trained in a one-trial inhibitory (passive) avoidance task, animals received an injection of PBZ or saline. Immediately after training, each animal received one of the following amnestic treatments: stimulation of the frontal cortex or amygdala, pentylenetetrazol, diethyldithiocarbamate, or cycloheximide. In control animals, each treatment produced retrograde amnesia. However, PBZ-treated animals did not develop amnesia. These findings suggest that there may be a common neurobiological mechanism underlying the amnesias produced by many treatments.

Alcohol-induced retrograde memory impairment in rats: prevention by caffeine.

RATIONALE: Ethanol and caffeine are two of the most widely consumed drugs in the world, often used in the same setting. Animal models may help to understand the conditions under which incidental memories formed just before ethanol intoxication might be lost or become difficult to retrieve. OBJECTIVES: Ethanol-induced retrograde amnesia was investigated using a new odor-recognition test. MATERIALS AND METHODS: Rats thoroughly explored a wood bead taken from the cage of another rat, and habituated to this novel odor (N1) over three trials. Immediately following habituation, rats received saline, 25 mg/kg pentylenetetrazol (a seizure-producing agent known to cause retrograde amnesia) to validate the test, 1.0 g/kg ethanol, or 3.0 g/kg ethanol. The next day, they were presented again with N1 and also a bead from a new rat's cage (N2). RESULTS: Rats receiving saline or the lower dose of ethanol showed overnight memory for N1, indicated by preferential exploration of N2 over N1. Rats receiving pentylenetetrazol or the higher dose of ethanol appeared not to remember N1, in that they showed equal exploration of N1 and N2. Caffeine (5 mg/kg), delivered either 1 h after the higher dose of ethanol or 20 min prior to habituation to N1, negated ethanol-induced impairment of memory for N1. A combination of a phosphodiesterase-5 inhibitor and an adenosine A(2A) antagonist, mimicking two major mechanisms of action of caffeine, likewise prevented the memory impairment, though either drug alone had no such effect. Binge alcohol can induce retrograde, caffeine-reversible disruption of social odor memory storage or recall.

Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity.

RATIONALE: Privileged episodic encoding of an aversive event often comes at a cost of neutral events flanking the aversive event, resulting in decreased episodic memory for these neutral events. This peri-emotional amnesia is amygdala-dependent and varies as a function of norepinephrine activity. However, less is known about the amnesiogenic potential of cortisol. OBJECTIVE: We used a strategy of pharmacologically potentiating cortisol and norepinephrine activity to probe the putative neurochemical substrates of peri-emotional amnesia. MATERIALS AND METHODS: Fifty-four healthy individuals participated in a randomized double-blind placebo-controlled study. Within the experimental context of an established peri-emotional amnesia paradigm, we tested the amnesiogenic potential of hydrocortisone (30 mg p.o.) in the presence or absence of the norepinephrine-reuptake inhibitor reboxetine (4 mg p.o.). RESULTS: Under dual challenge conditions, we observed a linear dose-response relationship in the magnitude and duration of emotion-induced retrograde amnesia. CONCLUSIONS: Our results are consistent with a phenotypic expression of retrograde amnesia varying as a function of norepinephrine and cortisol coactivation during episodic encoding of aversive events. Our study demonstrates that the adverse cognitive and behavioral sequelae of aversive emotion can be experimentally modeled by a pharmacological manipulation of its putative neurochemical substrates.

Noradrenergic modulation of emotion-induced forgetting and remembering.

We used a free-recall paradigm to establish a behavioral index of the retrograde and anterograde interference of emotion with episodic memory encoding. In two experiments involving 78 subjects, we show that negatively valenced items elicit retrograde amnesia, whereas positively valenced items elicit retrograde hypermnesia. These data indicate item valence is critical in determining retrograde amnesia and retrograde hypermnesia. In contrast, we show that item arousal induces an anterograde amnesic effect, consistent with the idea that a valence-evoked arousal mechanism compromises anterograde episodic encoding. Randomized double-blind administration of the beta-adrenoceptor antagonist propranolol compared with the selective norepinephrine (NE) reuptake-inhibitor reboxetine, and placebo, demonstrated that the magnitude of this emotional amnesia and hypermnesia can be upregulated and downregulated as a function of emotional arousal and central NE signaling. We conclude that a differential processing of emotional arousal and valence influences how the brain remembers and forgets.

Cilostazol but not sildenafil prevents memory impairment after chronic cerebral hypoperfusion in middle-aged rats.

We previously reported that the phosphodiesterase-5 (PDE5) inhibitor sildenafil prevented neurodegeneration but not learning deficits in middle-aged rats that were subjected to the permanent, three-stage, four-vessel occlusion/internal carotid artery (4-VO/ICA) model of chronic cerebral hypoperfusion (CCH). In the present study, we examined whether the PDE3 inhibitor cilostazol alleviates the loss of long-term memory (i.e., retrograde amnesia) caused by CCH. The effect of sildenafil was then compared to cilostazol. Naive rats (12-15 months old) were trained in a non-food-rewarded eight-arm radial maze and subjected to CCH. One week later, retrograde memory was assessed for 5 weeks. Cilostazol (50mg/kg, p.o.) was administered for 42 days or 15 days, beginning approximately 45 min after the first occlusion stage. Sildenafil (3mg/kg, p.o.) was similarly administered for 15 days only. Histological examination was performed after behavioral testing. Chronic cerebral hypoperfusion caused persistent retrograde amnesia, which was reversed by cilostazol after both short-term and long-term treatment. This antiamnesic effect of cilostazol was sustained throughout the experiment, even after discontinuing treatment (15-day treatment group). This effect occurred in the absence of neuronal rescue. Sildenafil failed to prevent CCH-induced retrograde amnesia, but it reduced hippocampal cell death. Extending previous findings from this laboratory, we conclude that sildenafil does not afford memory recovery after CCH, despite its neuroprotective effect. In contrast, cilostazol abolished CCH-induced retrograde amnesia, an effect that may not depend on histological neuroprotection. The present data suggest that cilostazol but not sildenafil represents a potential strategy for the treatment of cognitive sequelae associated with CCH.

Memory protective effect of indomethacin against electroconvulsive shock-induced retrograde amnesia in rats.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) have been suggested to retard cognitive decrements in patients with Alzheimer's disease. We postulated that NSAIDs also may protect acute disruption of memory. METHODS: We studied the effect of indomethacin (4 mg/kg/day) administered daily for 19 days on retrograde amnesia induced by two once-daily electroconvulsive shocks in rats. RESULTS: Indomethacin produced statistically significant prolongation of recall latency in a passive avoidance task using a step-down apparatus. CONCLUSIONS: Our study suggests that NSAIDs may prevent memory disruption through other mechanisms apart from attenuating chronic inflammation. In patients receiving electroconvulsive therapy, as in those diagnosed with Alzheimer's disease, antiinflammatory drugs may hold promise in the attenuation of cognitive impairments.

Naloxone in the prevention of the adverse cognitive effects of ECT: a within-subject, placebo controlled study.

Electroconvulsive therapy (ECT) is a highly effective treatment for major depression, but is also associated with characteristic cognitive side effects. Several reports document that endogenous opioids and their receptors are activated by electroconvulsive shock (ECS) and that naloxone in doses sufficient to block endogenous opioid receptors may reverse ECS-induced retrograde amnesia. This placebo-controlled, randomized, within-patient study was conducted to examine the potential of naloxone, given in doses sufficient to block opioid receptors (high dose), to ameliorate acute anterograde and retrograde memory impairments following ECT. Compared to placebo and low dose naloxone, high dose naloxone administered immediately before ECT resulted in significant reductions in anterograde amnesia, and better performance on an attention task. Both low and high dose naloxone improved verbal fluency. There were no beneficial effects of high dose naloxone on retrograde amnesia, and an indication that high dose naloxone may have worsened retrograde amnesia for shape stimuli. There were no effects of high dose naloxone on seizure duration, vital signs, and subjective side effects. The study is consistent with prior research in which change in behavioral and physiological measures was produced principally by naloxone doses sufficient to block endogenous opioid receptors and offers evidence of the potential for ameliorating some adverse cognitive effects associated with ECT.

Retrograde amnesia produced by electrical stimulation of the amygdala: attenuation with adrenergic antagonists.

Subseizure electrical stimulation of the amygdala produced retrograde amnesia for a visual discrimination shock-motivated task. Animals pretreated with the alpha-adrenergic antagonist phenoxybenzamine, or the beta-adrenergic antagonist propranolol, did not develop amnesia. The findings indicate that adrenergic antagonists attenuate amnesia produced by amygdala stimulation for visual discrimination training. These results are consistent with previous evidence indicating that adrenergic antagonists attenuate the amnesias produced by a variety of agents, and thus, suggest that adrenergic mechanisms may be involved in the production of retrograde amnesia.

Magnesium and ketamine attenuate cognitive dysfunction following experimental brain injury.

We evaluated the therapeutic effects of two noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, MgCl2 and ketamine, both individually and together, on cognitive dysfunction observed following parasagittal fluid-percussion (FP) brain injury in the rat. Using a modified Morris water maze technique, we found significant attenuation of post-traumatic memory dysfunction in animals treated with either MgCl2 (125 mumol) or ketamine (4 mg/kg) (P < 0.005). Combined MgCl2 and ketamine treatment also preserved memory function (P < 0.005), with no apparent additive effect.

Effect of RGH-2716 on learning and memory deficits of young and aged rats in water-labyrinth.

RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.

Retrograde amnesia produced by intrastriatal atropine and its reversal by choline.

A number of studies have shown that cholinergic blockade of the striatum produces amnesia. In the present experiment it was predicted that by increasing the synthesis of striatal acetylcholine such amnesic state would be prevented. Atropine was injected into the striatum of rats before training of passive avoidance; some of these rats were also injected, intrastriatally, with choline before testing the retention of the task. Atropine alone produced amnesia while the combination of treatments reversed this effect.

Effects of BN-50730 (PAF receptor antagonist) and physostigmine (AChE inhibitor) on learning and memory in mice.

The present study was designed to investigate the effect of BN-50730, a PAF receptor antagonist, on learning and memory in mice using elevated plus-maze and to delineate the role of acetylcholine in modulating the effect of PAF receptor antagonist on learning and memory. BN-50730 administered immediately after plus-maze training on day 1 induced retrograde amnesia as indicated by a dose-dependent increase in transfer latency (TL) measured on day 2 whereas no such increase in TL was noted when BN-50730 (2.5 mg/kg, i.p.) was administered prior to plus-maze training. Physostigmine (0.5 mg/kg; 1.0 mg/kg, i.p.) administered 30 min prior to plus-maze training attenuated BN-50730-induced increase in TL measured on day 2. These results suggest that BN-50730, a PAF receptor antagonist, produced retrograde amnesia and physostigmine attenuated BN-50730-induced amnesia possibly through increased concentration of cerebral acetylcholine and a consequent increase in PAF release.

Long-term effects of prior experience in attenuating amnesia.

In Experiment I, prior experience with passive-avoidance training followed by latent extinction was given 1, 3, 5, or 15 days before criterion (re) training and an amnesic treatment. It produced nearly complete protection from retrograde amnesia at the three shorter intervals; at the longest interval, amnesia was present but less severe than in a control group without the familiarization. In Experiment II, prior experience was given 1, 5, or 15 days before a noncontingent shock and an amnesic treatment. Evidence of a reactivation of memory was obtained only at the longest interval. Thus, familiarization and reactivation seem to represent different processes. The results are interpreted as consistent with explanations stressing the disruption of retrieval in retrograde amnesia.

[Effect of mental stimulants on electroconvulsive shock-induced retrograde amnesia]. / Wirkung von Nootropica auf die durch elektrokonvulsiven Schock ausgelöste retrograde Amnesie.

The effect of nootropics on the retrograde amnesia induced by electroshock was studied on a model of the active conditioned escape reaction (pole jumping). In untreated animals the daily application of electroshock for three days, immediately after the training, led to a significant retardation of the development of a conditioned escape reaction. The administration of nootropics influences the development of the retrograde amnesia to different extents, the treatment regimen (application of the drug only during the training and supplementary pretreatment before the first day of training; respectively) being of importance. The antiamnestic effect of Piracetam (100 mg/kg, intraperitoneally) which is good also without pretreatment, may still be potentiated, especially on the fourth day of treatment, by an additional administration of the drug, beginning four days before the first day of treatment. In contrast to this, meclofenoxate hydrochloride (100 mg/kg, intraperitoneally) and pyritinol (100 mg/kg, intraperitoneally) produce a marked inhibition of the development of the retrograde amnesia only after pretreatment. Without pretreatment these drugs exert a slight or no effect. The marked antiamnestic effect of methylglucaminorotate (225 mg/kg, intraperitoneally) and by an additional pretreatment. As to dihydroergotoxin (1 mg/kg; intraperitoneally), both treatment regimens were ineffective in the model used.

[A method for reproducing amnesia in mice by the complex extremal exposure]. / Metod vosproizvedeniia amnezii u myshei s pomoshch'iu kompleksnogo ékstremal'nogo vozdeistviia.

It is suggested to reproduce a retrograde amnesia in mice by means of a complex extremal action: emaciating swim in cold water with simultaneous wheel rotation. It was found that nootropes such as pyracetam, mexidol, semax, nooglutil, acephen, and noopept fully or completely prevent from the amnesia development.

[Pharmacological correction of memory impairment caused by a complex extremal action in mice with bilateral ligation of common carotid arteries]. / Farmacologicheskaia korrektsiia mnesticheskikh rasstroistv, vyzvannykh kompleksnym ékstremal'nym vozdeistiem u myshei s pereviazannymi oshchimi sonnymi arteriiami.

Semax and mexidol significantly increase the survival of white mongrel male mice upon bilateral ligation of common carotid arteries. Semax virtually completely prevented retrograde amnesia development in ligated mice under conditions of a complex extremal action (emaciating swim in cold water with simultaneous wheel rotation) and increased the lifetime of these animals in altitude test chamber.

Electroconvulsive therapy-induced persistent retrograde amnesia: could it be minimised by ketamine or other pharmacological approaches?

BACKGROUND: Certain pharmacological agents administered during electroconvulsive therapy may have the potential to prevent persistent retrograde amnesia induced during electroconvulsive therapy. This review examines mechanisms for electroconvulsive therapy-induced retrograde amnesia, and evaluates the suitability of the anaesthetic ketamine for preventing this amnestic outcome. METHODS: A review of human studies, animal models and theoretical models in light of memory dysfunction following electroconvulsive therapy was conducted. MEDLINE was searched from 1950 to April 2009 using the MeSH terms "electroconvulsive therapy", "memory", "memory short term", "memory disorders", "excitatory amino acid antagonists", and "ketamine". PREMEDLINE was searched using the terms "electroconvulsive therapy", "amnesia" and "ketamine". Additional keyword and reference list searches were performed. No language, date constraints or article type constraints were used. RESULTS: Disruption of long term potentiation as a mechanism for electroconvulsive therapy-induced retrograde amnesia is well supported. Based on this putative mechanism, an N-methyl-D-aspartate receptor antagonist would appear suitable for preventing the retrograde amnesia. Available evidence in animals and humans supports the prediction that ketamine, an anaesthetic agent and N-methyl-D-aspartate receptor antagonist, could effectively prevent electroconvulsive therapy-induced persistent retrograde amnesia. Whilst there are concerns about the use of ketamine with electroconvulsive therapy, such as possible psychotomimetic effects, on balance this anaesthetic agent may improve or hasten clinical response to electroconvulsive therapy. CONCLUSIONS: A clinical trial is warranted to determine if ketamine anaesthesia during electroconvulsive therapy can lessen persistent retrograde amnesia and improve therapeutic response. Electroconvulsive therapy with ketamine anaesthesia may provide effective antidepressant action with minimal side effects.