The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models.

BACKGROUND AND PURPOSE: Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH: Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS: MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS: MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Combined application of tenuigenin and ß-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of ß-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. PATIENTS AND METHODS: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received ß-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5-20 mg/d. Patients in the control group only received memantine 5-20 mg/d. The Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Activities of Daily Living (ADL) were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks. RESULTS: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001), lower average ADL score (p=0.00002), and lower average CDR score (p=0.030). Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60-74-years-old male patients with moderate AD. CONCLUSION: These results demonstrated that the combined application of ß-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored.

Efficacy of tenuigenin and ß-asarone as augmentations for memantine in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that has no cure at present. This study was carried out to evaluate whether the combination of ß-asarone and tenuigenin could improve the efficacy of memantine as a monotherapy in the treatment of AD. Patients with AD were recruited and assigned to two groups. Patients in the control group received memantine (5-20 mg/day) and those in the experimental group received memantine (5-20 mg/day), ß-asarone (20 mg/day), and tenuigenin (20 mg/day). The Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Clinical Dementia Rating Scale (CDR) scores and drug-related side-effects were assessed. Treatment was continued for 12 weeks. In total, 93 AD patients (45 in the control group and 48 in the experimental group) were recruited. Before treatment, both the groups had similar average MMSE scores, ADL scores, and CDR scores, whereas all the average scores improved significantly after treatment. However, compared with the control group, the experimental group had a significantly higher average MMSE score (P=0.00001) and lower average ADL (P=0.00604) and CDR (P=0.00776) scores after treatment. Moreover, the two groups had similar rates of drug-related side-effects. These results indicated that the combination of ß-asarone and tenuigenin was an effective augmentation for memantine in the treatment of AD and did not cause more drug-related side-effects. This novel method is worthy of further investigation.

GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers.

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels that mediate excitatory synaptic transmission. Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes. Here, we report a de novo recurrent heterozygous missense mutation-c.1999G>A (p.Val667Ile)-in a NMDAR gene previously unrecognized to harbor disease-causing mutations, GRIN2D, identified by exome and candidate panel sequencing in two unrelated children with epileptic encephalopathy. The resulting GluN2D p.Val667Ile exchange occurs in the M3 transmembrane domain involved in channel gating. This gain-of-function mutation increases glutamate and glycine potency by 2-fold, increases channel open probability by 6-fold, and reduces receptor sensitivity to endogenous negative modulators such as extracellular protons. Moreover, this mutation prolongs the deactivation time course after glutamate removal, which controls the synaptic time course. Transfection of cultured neurons with human GRIN2D cDNA harboring c.1999G>A leads to dendritic swelling and neuronal cell death, suggestive of excitotoxicity mediated by NMDAR over-activation. Because both individuals' seizures had proven refractory to conventional antiepileptic medications, the sensitivity of mutant NMDARs to FDA-approved NMDAR antagonists was evaluated. Based on these results, oral memantine was administered to both children, with resulting mild to moderate improvement in seizure burden and development. The older proband subsequently developed refractory status epilepticus, with dramatic electroclinical improvement upon treatment with ketamine and magnesium. Overall, these results suggest that NMDAR antagonists can be useful as adjuvant epilepsy therapy in individuals with GRIN2D gain-of-function mutations. This work further demonstrates the value of functionally evaluating a mutation, enabling mechanistic understanding and therapeutic modeling to realize precision medicine for epilepsy.

Anti-Dementia Drugs, Gait Performance and Mental Imagery of Gait: A Non-Randomized Open-Label Trial.

BACKGROUND: Few studies have examined the effect of anti-dementia drugs (i.e., acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists) on gait performance. Past studies have focused on the stride time (i.e., gait cycle duration) but not on the mental imagery of gait. OBJECTIVES: To compare mental imagery of gait and spatiotemporal gait parameters in patients with dementia [i.e., Alzheimer's disease (AD) and non-AD] before and after the use of anti-dementia drugs (i.e., acetylcholinesterase inhibitors and memantine) and in controls (i.e., patients with dementia who did not take anti-dementia drugs). METHODS: A total of 112 patients (mean age 82.5 ± 4.2 years, 68.8 % female) with mild-to-moderate AD and non-AD dementia were included in this non-randomized open-label trial (n = 56 in the Intervention group, and n = 56 in the Control group matched for age, sex, and stage and type of dementia) nested in a cohort study (mean follow-up 238.5 ± 79.8 days). Mental imagery of gait was assessed with the actual and imagined Timed Up and Go tests (aTUG and iTUG) and the difference between aTUG and iTUG (i.e., delta-TUG). Spatiotemporal gait parameters were measured with the GAITRite(®) system during normal walking. RESULTS: Participants in the Intervention group had a longer iTUG time (p < 0.001) and a lower delta-TUG value (p = 0.001) at the follow-up compared with those in the Control group. There was a significant increase in iTUG (p = 0.001) and decrease in delta-TUG (p < 0.001) from baseline to the follow-up only in the Intervention group. Multiple linear regression showed that the use of anti-dementia drugs was associated with a longer iTUG time and a lower delta-TUG value (best performance, p < 0.002). CONCLUSIONS: Our findings showed an improvement in mental imagery of gait with the use of anti-dementia drugs, but no changes in actual gait performance. TRIAL REGISTRATION: NCT01315704.

The potent effects of ginseng root extract and memantine on cognitive dysfunction in male albino rats.

The study determined the maximum intraperitoneal (ip) scopolamine dose inducing memory impairment in rats (2 mg/kg) compared to 0.5 or 1 mg/kg dose. The effect reflected by significant increase from normal in the latency time required for rats to find the hidden platform in water maze task and acetylcholinesterase (AChE) activities in cortex, hippocampus and striatum. The dose-related histopathological effect via the hemorrhage, vacuolation and gliosis in cortex and hippocampus is assessed. Then the study investigated the potency of Panax ginseng root extract on scopolamine cognitive dysfunction rat model compared to memantine hydrochloride as reference Food and Drug Administration approved. Ginseng extract was administered at dose 100 or 200 mg/kg/day and memantine at 20 mg/kg/day orally for 2 weeks. All treatments showed improvement in the water maze task, however, ginseng (200 mg/kg) group acquired the advantage without statistical difference control. Scopolamine (2 mg/kg ip) group showed significant increase in AChE reactivity and glutamate level and reduced monoamines (norepinephrine, dopamine and serotonin) and γ-aminobutyric acid contents in cortex, hippocampus and striatum. Ginseng extract in a dose-dependent manner appears effective as memantine and can improve memory impairment through the retrieved homeostasis via neurotransmitter levels and AChE activities in rat brain areas with partial effect on the histological feature of the brain tissue.

[Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats].

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.

An immunohistochemical analysis of the neuroprotective effects of memantine, hyperbaric oxygen therapy, and brimonidine after acute ischemia reperfusion injury.

PURPOSE: This study applies treatment methods to rat retinas subjected to acute ischemia reperfusion injury and compares the efficacy of memantine, hyperbaric oxygen (HBO) therapy, and brimonidine by histopathological examination. METHODS: Thirty adult Wistar albino rats were divided into five groups after retinal ischemia was induced by elevating the intraocular pressure to 120 mmHg. The groups were as follows: group 1: control; group 2: acute retinal ischemia (ARI) model but without treatment group; group 3: memantine (MEM) treatment group; group 4: HBO therapy group; and group 5: brimonidine treatment (BRI) group. In the control group, right eyes were cannulated with a 30-gauge needle and removed without causing any intraocular pressure change. The ARI group was an acute retinal ischemia model, but without treatment. In the MEM group, animals were given a unique dose of intravenous 25 mg/kg memantine by the tail vein route after inducing ARI. In the HBO group, at 2 h following ARI, HBO treatment was applied for nine days. In the BRI group, a 0.15% brimonidine tartrate eye drop treatment was applied twice a day (BID) for seven days before ARI. Twenty-one days after establishing ischemia reperfusion, the right eyes were enucleated after the cardiac gluteraldehyde perfusion method, and then submitted to histological evaluation. RESULTS: On average, the total retinal ganglion cell number was 239.93 ± 8.60 in the control group, 125.14 ± 7.18 in the ARI group, 215.89 ± 8.36 in the MEM group, 208.69 ± 2.05 in the HBO group, and 172.27 ± 8.16 in the BRI group. Mean apoptotic indexes in the groups were 1.1 ± 0.35%, 57.71 ± 0.58%, 23.57 ± 1.73%, 15.63 ± 0.58%, and 29.37 ± 2.55%, respectively. CONCLUSIONS: The present study shows that memantine, HBO, and brimonidine therapies were effective in reducing the damage induced by acute ischemia reperfusion in the rat retina. Our study suggests that these treatments had beneficial effects due to neuroprotection, and therefore may be applied in clinical practice.

Antidementia drug prescription sources and patterns after the diagnosis of dementia in Germany: results of a claims data-based 1-year follow-up.

We examined the patterns of prescription for antidementia drugs by German physicians with special reference to source of prescription, appropriateness of drugs and dosages and continuity of prescription patterns. The study is based on claims data of all 1848 incident cases in persons aged 65 years and older from a nationwide operating statutory health insurance company in the years 2004-2006. Inclusion criteria were one International Statistical Classification of Diseases and Related Health Problems 10th Revision code for dementia in at least three of four consecutive quarters and four quarters without such a code beforehand. Defined daily doses were used to quantify the prescription size. Data analysis used univariate and multivariate techniques. The majority of incident dementia cases in general and Alzheimer's disease cases in particular did not receive medication in conformity with the guidelines during the year after incidence. Inappropriate prescription was related to not visiting a specialist, living in urban areas, age and comorbidity. Further research is needed both on reasons for nonprescription among professionals and for discontinuation by the patients. In addition, the problems of practicability and implementation of guidelines deserve more attention.

A 1H-MR spectroscopy study of changes in glutamate and glutamine (Glx) concentrations in frontal spectra after administration of memantine.

Glutamate is the major excitatory neurotransmitter in the brain and therefore important for cognitive functions. The aim of the study was to investigate if administration of the N-methyl-D-aspartate receptor antagonist memantine to healthy individuals would affect brain activation when performing an auditory attention task. The task was a variant of a dichotic listening task with different instructions that tap demands for attention and cognitive control. We asked the question if memantine administration would lead to reduction in glutamatergic neurotransmission in areas related to attention and cognitive control. Left and right frontal glutamate and glutamine (Glx) concentrations were measured, using (1)H-MR spectroscopy. Twenty-five healthy adults were scanned twice in a counterbalanced design, either drug naive or after administration of memantine for 21 days. The results showed that memantine significantly reduced Glx concentrations, and this reduction was associated with a reduction in brain activation in prefrontal cortex, which could have implications for understanding the neuronal mechanisms underlying higher cognitive functions such as cognitive control.

[Effects of memantine on convulsive reactions and sleep-waking cycle in Krushinskii-Molodkina strain rats with the inherited predisposition to audiogenic convulsions].

Krushinskii-Molodkina strain rats have an inherited predisposition to audiogenic convulsions and are used as a natural animal model in the anticonvulsive drugs studies. We have investigated whether changes in the glutamatergic synaptic transmission are involved in the mechanism of audiogenic convulsions and functional organization of sleep-waking cycle observed in rats of this line. For this purpose Memantine, a selective uncompetitive blocker of NMDA receptors was used. Memantine was injected i.m. at the dose 5 or 10 mg/kg injected 30 min, 1, 2 or 3 hours before the sound stimulus (the sine-wave tone 8 kHz, 90 db). We evaluated the latent period of initial enhanced motor activity, the appearance and intensity of clonic seizures, and thereafter the tonic seizures accompanied by extension of limbs and tail. The maximal attenuation of convulsive attack to the level of initial motor excitement only was occurred in 60% of rats between 1 and 2 hours after memantine pretreatment. No difference between the doses 5 and 10 mg/kg was observed. The effect of memantine began to decrease when memantine was injected 3 h before convulsion provocation. The recording of EEG by chronically implanted electrodes was performed from the rats of Krushinsky-Molodkina line for the study of memantine effects on the sleep organization. The sleep of these rats during the first hour after 5 or 7 mg/kg memantine injection exhibited as the short periods of slow-wave sleep only which disappeared completely thereafter 54.4 +/- 4.9 and 39.9 +/- 5.2 min correspondingly. The complete sleep loss was observed approximately 2-2.5 hours later and followed by appearance of episodes of slow-wave sleep. The first episodes of fast-wave sleep occurred 3-4 hours later. Their reappearance evidenced of the completion of memantine action on the somnogenic brain systems and the beginning of recovery of normal sleep-waking organization. Thus the manifestations of unidirectional and synchronous memantine action on audiogenic seizures and disturbances of sleep-waking mechanisms may speak about involvement of NMDA receptors in both of epileptogenesis and somnogenic system of Krushinsky-Molodkina rats line.

Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity.

NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca(2+)homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti-inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3-microL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, reactive oxygen species production, mitochondrial membrane potential (Delta Psi m), mitochondrial reductase activity (MTT test), and Ca(2+)concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (Delta Psi m) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS-sensitive Na(+), K(+)-ATPase and Mg(2+)-ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, the mitochondrial membrane potential (Delta Psi m), the mitochondrial reductase activity, and the increased synaptosomal Ca(2+)concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.

In vitro galantamine-memantine co-application: mechanism of beneficial action.

Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors. We have recently found that galantamine potentiates the activity of NMDA receptors as well. Memantine is unique in that it inhibits the NMDA receptors. We have developed a hypothesis that combining galantamine and memantine will be more effective for improving the patient's conditions than monotherapy with either drug. Patch clamp and intracellular Ca(2+) imaging experiments using rat cortical and hippocampal neurons clearly provided the in vitro bases for our hypothesis. Memantine blocked the extrasynaptic NMDA receptor 100 times more potently than the synaptic NMDA receptor at negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage dependent. Thus, co-application of memantine with galantamine prevented the galantamine potentiation and the activation of extrasynaptic NMDA receptors, but membrane depolarization revealed the galantamine potentiation. Therefore, cell death is expected to be prevented by memantine near the resting potential while the NMDA-mediated synaptic transmission, which is down-regulated in the patients, is maintained and potentiated by galantamine. These results provide in vitro bases for the beneficial actions of galantamine and memantine combinations.

[Current therapy of patients with dementia]. / Aktuelle Antidementiva. Demenzkranken steht eine moderne Therapie zu.

In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are being investigated in ongoing clinical and experimental studies. Presently available treatments should be initiated early on, and applied as long as needed, which requires the earliest possible clinical diagnosis by the primary-care physician. The results of initial studies reveal an effect of antidementia agents also in mixed Alzheimer's and vascular dementia, as well as vascular and lewy-body dementia. Efforts to obtain approval for these indications are underway.

[Current strategies of pathogenetic therapy of Alzheimer's disease]. / Sovremennye strategii patogeneticheskoi terapii bolezni Al'tsgeimera.

This is a review of the data available in the literature and the authors' own findings on pathogenetical rationale for the use and clinical study of current treatments for Alzheimer's disease (AD) (synonym: Alzheimer-type dementia). In the past decade many attempts have been made at targeting different links of the pathogenesis of a neurodegenerative process that underlie AD. Several areas of pathogenetical therapy for AD have been developed on the basis of experimental studies and pilot clinical tests. The most developed areas are as follows: various compensatory (replacement) treatments aimed at overcoming neurotransmitter deficit in different neuronal systems that are damaged in AD to a greater or lesser extent; neuroprotective therapy promoting increased viability (survival) of neurons and their plasticity, and vasoactive therapy. Rather new directions of AD pathogenetic therapy, such as antiinflammatory and hormonal therapy along with antiamyloid therapeutic strategies are still under study.