g(m1)-ganglioside and Cognition-Disorders

Many neuroprotective agents (NPAs) are effective in acute experimental cerebral ischemia in animals. None have proven effective in human stroke trials. Even short treatment delays cause substantial efficacy loss. Cardiac surgery under cardiopulmonary bypass (CS-CPB) causes cerebral ischemia with cognitive impairment at a predeterminable time point and should permit efficient screening of NPAs for stroke benefit. We sought to develop sensitive methods to assess dysfunction from CS-CPB in a double-blind trial of the NPA GM1 ganglioside.. Eighteen GM1 and 11 Control patients received GM1 300 mg or placebo, two doses intravenously, before nonemergency CS-CPB. Independent examiners administered structured neurological examinations and neuropsychological test batteries at Baseline and 1 day (Acute Postop; neurological only), 1 week (Early F/U), and > or = 6 months (Long-term F/U) postoperatively; using defined procedures they employed ordinal Clinical Change Scores (CCSs) to quantify neurological cerebral, neurological noncerebral, and neuropsychological performance changes. Several methods to analyze CCSs and neuropsychological test score changes were evaluated.. The most sensitive indicators were the mean Acute Postop Neurologist's CCS-Cerebral (P < 10(-5)) and the mean Early F/U Neuropsychologist's CCS (P < .01), with statistically nonsignificant differences favoring GM1. No significant mean changes in Neurologist's CCS-Noncerebral or any Long-term F/U CCSs occurred. CCS distributions and neuropsychological test score mean changes showed similar temporal patterns, with less sensitivity to change. When, as usual in prior CS-CPB studies, impairment was defined by neuropsychological test score declines (increases ignored), results were spurious.. The strokelike cerebral dysfunction (maximal acutely, with eventual recovery) that occurs after CS-CPB is useful to screen NPAs for clinical efficacy. CCSs based on detailed neurological examination and neuropsychological testing are sensitive measures; refinement of this approach should enhance the efficiency of the CS-CPB model. Further testing of GM1 is warranted.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiopulmonary Bypass; Cognition; Cognition Disorders; Coronary Artery Bypass; Coronary Disease; Double-Blind Method; Female; Follow-Up Studies; G(M1) Ganglioside; Heart Valve Prosthesis; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Placebos; Postoperative Complications; Probability; Sensitivity and Specificity; Time Factors

Traumatic Brain Injury (TBI) is one of the most common causes of neurological damage in young populations. It has been previously suggested that one of the mechanisms that underlie brain injury is Axonal Outgrowth Inhibition (AOI) that is caused by altered composition of the gangliosides on the axon surface. In the present study, we have found a significant reduction of GM1 ganglioside levels in the cortex in a closed head traumatic brain injury model of a mouse, induced by a weight drop device. In addition, axonal regeneration in the brains of the injured mice was affected as seen by the expression of the axonal marker pNF-H and the growth cones (visualized by F-actin and β-III-tubulin). NeuN immunostaining revealed mTBI-induced damage to neuronal survival. Finally, as expected, spatial and visual memories (measured by the Y-maze and the Novel Object Recognition tests, respectively) were also damaged 7 and 30 days post injury. A single low dose of GM1 shortly after the injury (2 mg/kg; IP) prevented all of the deficits mentioned above. These results reveal additional insights into the neuroprotective characteristics of GM1 in prevention of biochemical, cellular and cognitive changes caused by trauma, and may suggest a potential intervention for mTBI.

Topics: Animals; Axons; Brain Injuries, Traumatic; Cognition Disorders; Disease Models, Animal; G(M1) Ganglioside; Male; Mice; Mice, Inbred ICR; Neurodegenerative Diseases; Neuroprotective Agents

Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; G(M1) Ganglioside; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction

In this study, we used GM2/GD2 synthase knockout (GM2/GD2−/−) mice to examine the influence of deficiency in ganglioside “a-pathway” and “b-pathway” on cognitive performances and hippocampal synaptic plasticity. Eight-week-old GM2/GD2−/− male mice showed a longer escape-latency in Morris water maze test and a shorter latency in step-down inhibitory avoidance task than wild-type (WT) mice. Schaffer collateral-CA1 synapses in the hippocampal slices from GM2/GD2−/− mice showed an increase in the slope of EPSPs with reduced paired-pulse facilitation, indicating an enhancement of their presynaptic glutamate release. In GM2/GD2−/− mice, NMDA receptor (NMDAr)-dependent LTP could not be induced by high-frequency (100–200 Hz) tetanus or θ-burst conditioning stimulation (CS), whereas NMDAr-independent LTP was induced by medium-frequency CS (20–50 Hz). The application of mono-sialoganglioside GM1 in the slice from GM2/GD2−/− mice, to specifically recover the a-pathway, prevented the increased presynaptic glutamate release and 20 Hz-LTP induction, whereas it could not rescue the impaired NMDAr-dependent LTP. These findings suggest that b-pathway deficiency impairs cognitive function probably through suppression of NMDAr-dependent LTP, while a-pathway deficiency may facilitate NMDAr-independent LTP through enhancing presynaptic glutamate release. As both of the NMDAr-independent LTP and increased presynaptic glutamate release were sensitive to the blockade of L-type voltage-gated Ca2+ channels (L-VGCC), a-pathway deficiency may affect presynaptic L-VGCC.

Topics: Animals; Avoidance Learning; CA1 Region, Hippocampal; Calcium; Cognition Disorders; Electric Stimulation; Excitatory Postsynaptic Potentials; G(M1) Ganglioside; In Vitro Techniques; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Mice; Mice, Knockout; N-Acetylgalactosaminyltransferases; Neuronal Plasticity; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission

The functional consequences of cortical focal ischemia and the effect of monosialoganglioside (GM1) treatment on learning/performance of a spatial reversal task were investigated. Cortical focal ischemia was induced by a permanent occlusion of the left common carotid artery and the ipsilateral middle cerebral artery, with a 1-h clamping of the contralateral carotid artery. Twenty-six rats were randomly assigned to three groups: sham controls, a saline-treated ischemic group, and a GM1 ganglioside-treated ischemic group (10 mg/kg/day: IM). Fifteen days after surgery rats were trained on a spatial reversal task in a two-lever operant chamber where food reward was contingent on lever pressing. Training continued from day 15 to day 21 after surgery. Cortical focal ischemia resulted in learning/performance deficits that were reduced by GM1 ganglioside treatment. The cognitive deficits were characterized by a significantly higher number of nonperseverative errors and number of responses to criterion. There was a significant difference between left and right lever performance in the saline-treated ischemic group, which was absent in shams and GM1-treated ischemic rats. On all measures GM1-treated rats were not different from sham controls.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cognition Disorders; Conditioning, Operant; Food; G(M1) Ganglioside; Male; Psychomotor Performance; Rats; Rats, Inbred Strains; Reversal Learning; Reward; Space Perception