Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease

This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy—with the N-methyl-d-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)—for the treatment of Alzheimer’s disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually

Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse‑effect potential

Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L‑DOPA‑induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice‑daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200–500 nM plasma concentrations. In the elevated plus maze eltoprazine increased anxiety‑like behavior. On the other hand, it induced a clear‑cut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test. Regarding adverse effects, eltoprazine was found to produce hypothermia starting from 1 mg/kg. At similar doses it also increased locomotion in the open field. However, eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg). In summary, effects of eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects

Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity

Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets

Modulation of l-DOPA-induced abnormal involuntary movements by clinically tested compounds: Further validation of the rat dyskinesia model.

l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's Disease. A model of LID has recently been described in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In the present study, the model was used in order to compare the efficacies of some clinically available compounds that have shown antidyskinetic effects in nonhuman primate models of LID and/or in patients, namely, amantadine (20 and 40 mg/kg), buspirone (1, 2 and 4 mg/kg), clonidine (0.01, 0.1 and 1 mg/kg), clozapine (4 and 8 mg/kg), fluoxetine (2.5 and 5 mg/kg), propranolol (5, 10 and 20 mg/kg), riluzole (2 and 4 mg/kg), and yohimbine (2 and 10 mg/kg). Rats were treated for 3 weeks with l-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs) prior to the drug screening experiments. The antidyskinetic drugs or their vehicles were administered together with l-DOPA, and their effects were evaluated according to a randomized cross-over design both on the AIM rating scale and on the rotarod test. Most of the compounds under investigation attenuated the l-DOPA-induced axial, limb and orolingual AIM scores. However, the highest doses of many of these substances (but for amantadine and riluzole) had also detrimental motor effects, producing a reduction in rotarod performance and locomotor scores. Since the present results correspond well to existing clinical and experimental data, this study indicates that axial, limb and orolingual AIMs possess predictive validity for the preclinical screening of novel antidyskinetic treatments. Combining tests of general motor performance with AIMs ratings in the same experiment allows for selecting drugs that specifically reduce dyskinesia without diminishing the anti-akinetic effect of l-DOPA

Analysis of two methods indicating the shoulder joint angles using three dimensional data

The article contains a comparative analysis of two methods of calculating angles in the shoulder joint of the right upper limb. For the purposes of this study, a marker -vector method was developed that calculates angles based on retroreflective 3D marker’s positions and vectors created on the basis of their positions. Movements from two types of sports (sword fighting and tennis forehand) were analysed. These movem ents were recorded using an optical motion capture system. The obtained results were compared with the values read from the Plug -in Gait biomechanical model from C3D files. The results show that the proposed method is more universal and can be used indepen dently. In addition, the Plug -in Gait model is not adequate for the analysis of the acquired shoulder angles of tennis players

Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson's disease

The present study was devoted to investigate the effects of the metabotropic glutamate receptor(mGluR)5 antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and the mGluR1 antagonist, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), in animal studies indicative of antiparkinsonian-like activity such as haloperidol-induced catalepsy, hypoactivity in open field following haloperidol, and rotation in rats with unilateral 6-hydroxydopamine(OHDA)-induced lesions of the midbrain dopaminergic system (alone and in combination with L-DOPA). Moreover, antidyskinetic activity of different mGluR ligands was evaluated in the rat model of L-DOPA-induced dyskinesia. Both MTEP (5 mg/kg) and EMQMCM (4 mg/kg) slightly inhibited haloperidol (0.5 mg/kg)-induced catalepsy. However, neither substance reversed the hypoactivity produced by haloperidol (0.2 mg/kg). Although MTEP and not produce significant turning, it inhibited contralateral rotations after L-DOPA (at 5 mg/kg) and alleviated L-DOPA-induced dyskinesia (at 2.5 and 5 mg/kg) in 6-OHDA-lesioned rats. In contrast, mGluR1 antagonists EMQMCM and RS-1-aminoindan-1,5-dicarboxylic acid (AIDA) failed to modify L-DOPA-induced dyskinesia. The results of the present study suggest that either subtype of group I of mGluRs may be involved in the pathologically altered circuitry in the basal ganglia. However, the equivocal results do not strongly support the hypothesis that mGluR1 and mGluR5 antagonists may be beneficial in the symptomatic treatment of Parkinson's disease. However, mGluR5 antagonists may prove useful for the symptomatic treatment Of L-DOPA-induced dyskinesia. (c) 2006 Elsevier Inc. All rights reserved

Deficit of endogenous kynurenic acid in the frontal cortex of rats with a genetic form of absence epilepsy

Item does not contain fulltextThe present studies sought to determine the concentrations of endogenous kynurenic acid (KYNA) and to measure the activity of kynurenine aminotransferases (KAT) I and II in the discrete brain regions of 3- and 6-month old WAG/Rij rats, a genetic model of absence epilepsy. Analogues experiments were performed using age-matched ACI rats, which served as a non-epileptic control. The age-dependent increase in KYNA concentration in the frontal cortex of WAG/Rij rats was considerably reduced in comparison to what was found in ACI rats. Consequently, the concentration of KYNA in the frontal cortex of epileptic rats was significantly lower than in non-epileptic controls. There were no such strain differences in other brain regions. The activities of KAT I and II also showed age-dependent increase with an exception for KAT II in the frontal cortex. Our data suggest that selective deficits of endogenous KYNA may account for increased excitability in the frontal cortex, which in turn may lead to the development of spontaneous spike-wave discharges in WAG/Rij rats