PierFranco Spano

Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study

BACKGROUND Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia. METHODS A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis. FINDINGS Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable. INTERPRETATION Rivastigmine 6-12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.

Neuroprotection by Aspirin and Sodium Salicylate Through Blockade of NF-κB Activation

Aspirin (acetylsalicylic acid) is a commonly prescribed drug with a wide pharmacological spectrum. At concentrations compatible with amounts in plasma during chronic anti-inflammatory therapy, acetylsalicylic acid and its metabolite sodium salicylate were found to be protective against neurotoxicity elicited by the excitatory amino acid glutamate in rat primary neuronal cultures and hippocampal slices. The site of action of the drugs appeared to be downstream of glutamate receptors and to involve specific inhibition of glutamate-mediated induction of nuclear factor kappa B. These results may contribute to the emerging theme of anti-inflammatory drugs and neurodegeneration.

Dopamine receptors: Pharmacological and anatomical evidences indicate that two distinct dopamine receptor populations are present in rat striatum

(3H)-haloperidol and (3H)-spiroperidol binding studies after kainate injection into the striatum indicate the presence of dopamine receptive sites not located on post-synaptic membranes. The majority of these dopamine “receptors” which are not associated to an adenylate cyclase appear to be localized on terminals of cortico-striatal neurons. On the other hand sulpiride, an antipsychotic drug which increases striatal dopamine synthesis, does not inhibit dopamine-stimulated adenylate cyclase either in vitro or in vivo. However sulpiride stereospecifically displaces (3H)-haloperidol from striatal binding sites.

Effects of rivastigmine on cognitive function in dementia with lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system.

This study was designed to assess the effects of rivastigmine (Exelon®) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, patients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.

SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease

The pre-synaptic protein alpha-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinsons disease and dementia with Lewy bodies. Mutations in the alpha-synuclein gene cause familial forms of Parkinsons disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human alpha-synuclein(1-120) that develops alpha-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinsons disease. We now show that in the striatum of these mice, as in Parkinsons disease, synaptic accumulation of alpha-synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length alpha-synuclein(1-140) or truncated alpha-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of alpha-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinsons disease.

Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection

The role of group-I metabotropic glutamate receptors (mGlu1 and 5) in neurodegeneration is still controversial. While antagonists of these receptors are consistently neuroprotective, agonists have been found to either amplify or attenuate excitotoxic neuronal death. At least three variables affect responses to agonists: (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of an activity-dependent functional switch of group-I mGlu receptors, similar to that described for the regulation of glutamate release; and (iii) the presence of astrocytes expressing mGlu5 receptors. Thus, a number of factors, including the heteromeric composition of NMDA receptors, the exposure time to drugs or to ambient glutamate, and the function of astrocytes clearing extracellular glutamate and producing neurotoxic or neuroprotective factors, must be taken into account when examining the role of group-I mGlu receptors in neurodegeneration/neuroprotection.

Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization.

Colocalization of dopamine D1 (D1R) and D3 receptors (D3R) in specific neuronal populations suggests that their functional cross-talk might involve direct interactions. Here we report that the D1R coimmunoprecipitates with the D3R from striatal protein preparations, suggesting that they are clustered together in this region. Using bioluminescence resonance energy transfer (BRET2), we further suggest the existence of a physical interaction between D1R and D3R. Tagged D1R and D3R cotransfected in human embryonic kidney (HEK) 293 cells generated a significant BRET2 signal that was insensitive to agonist stimulation, suggesting that they form a constitutive heterodimer. D1R and D3R regulate adenylyl cyclase (AC) in opposite ways. In HEK 293 cells coexpressing D1R and D3R, dopamine stimulated AC with higher potency and displaced [3H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) binding with higher affinity than in cells expressing the D1R. In HEK 293 cells individually expressing D1R or D3R, agonist stimulation induces internalization of D1R but not of D3R. Heterodimerization with D3R abolishes agonist-induced D1R cytoplasmic sequestration induced by selective D1R agonists and enables internalization of the D1R/D3R complex in response to the paired stimulation of both D1R and D3R. This mechanism involves β-arrestin binding because it was blocked by mutant β-arrestinV53D. These data suggest that as a result of dimerization, the D3R is switched to the desensitization mechanisms typical of the D1R. These data give a novel insight into how D1R and D3R may function in an integrated way, providing a molecular mechanism by which to converge D1R- and D3R-related dysfunctions.

Dopamine Uptake is Differentially Regulated in Rat Striatum and Nucleus Accumbens

Abstract: Active uptake of 3,4‐dihydroxyphenylethylamine (dopamine) is sodium‐ and temperature‐dependent, strongly inhibited by benztropine and nomifensine, and present in corpus striatum and nucleus accumbens. In rat striatum dopamine uptake is related to a receptor that is specifically labelled by [3H]cocaine in the presence of Na+ and is located on dopaminergic terminals. The dopamine uptake is differentially affected in the two areas by single or repeated injections of cocaine. Cocaine inhibits dopamine uptake in slices of corpus striatum. Moreover Na+‐dependent [3H]cocaine binding is not detectable in nucleus accumbens. Nomifensine inhibits [3H]dopamine uptake by interacting with low‐ and high‐affinity sites in corpus striatum, but shows only low affinity for dopamine uptake in nucleus accumbens. The present data indicate that different mechanisms are involved in the regulation of dopamine uptake in corpus striatum and nucleus accumbens.

A dopamine-stimulated adenylate cyclase in rat substantia nigra

THL PKLSENCE of dopamine (DA) receptors in the substantia nigra was first suggested by AGHAJANIAN & BUNNEY (1973) on the basis of microiontophoretic results. These authors showed that dopamine and the dopaminemimetic compound apomorphine, when applied by microiontophoresis to cell bodies of the substantia nigra. are able to inhibit the unit firing of these neurons (BUNNEY & AGHAJANIAN, 1975). In addition to these data are the histochemical observations of BJORKLLIND & LINDVALL (1975) and PARIZEK et ul. (1971) on the terminal dendritic processes of dopamine cell bodies in the nigra. These authors demonstrated that dopamine is stored in the extensive dendritic processes of dopaminergic perikarya. Moreover the same authors showed that an uptake mechanism for dopamine is present in the dendrites. More recently GEFFEN er 01. (1976) and KORF et a/. (1976) have provided evidence for the release of DA from dendrites of dopaminergic neurons in rat substantia nigra. On the basis of these observations, it has been proposed that a local dendritic release of DA may have a number of functions in the substantia nigra neuronal network. In this study we have found that a n adenylate cyclase which is preferentially stimulated by dopamine is present in the substantia nigra of rat brain. We suggest that the dopamine-stimulated adenylate cyclase of substantia nigra may be part of a receptor mechanism for the pool of dopamine released from the dendrites of dopaminergic neurons. Therefore, the dopamine-stimulated adenylate cyclase of the substantia nigra may provide a highly specific model for studying dopamine receptor function in this area.

Attenuation of Excitatory Amino Acid Toxicity by Metabotropic Glutamate Receptor Agonists and Aniracetam in Primary Cultures of Cerebellar Granule Cells

Abstract: Activation of glutamate ionotropic receptors represents the primary event in the neurotoxicity process triggered by excitatory amino acids. We demonstrate here that the concentration‐dependent stimulation of metabotropic glutamate receptor (mGluR) by the selective agonist trans‐1‐aminocyclopentane‐1, 3‐dicarboxylate or by quisqualate counteracts both glutamate‐ and kainate‐induced neurotoxicity in primary cultures of rat cerebellar granule cells. The mGluR‐evoked responses are potentiated by aniracetam, which per se also elicits neuroprotection. Aniracetam concentration‐dependently counteracted glutsmate‐, kainate‐, or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid‐induced cell death and greatly facilitated neuroprotective response achieved by different concentrations of both quisqualate and trans‐1‐aminocyclopentane‐1, 3‐dicarboxylate. In addition, aniracetam potentiated the mGluR‐coupled stimulation of phospholipase C, as revealed by the measurement of 3H‐inositol phosphate formation. Thus, mGluRs could be a suitable target for novel pharmacological strategies pointing to the treatment of neurodegenerative diseases.