Michel Reibaud

Enhancement of memory in cannabinoid CB1 receptor knock-out mice.

We have used cannabinoid CB knock-out mice in a two-trial object recognition test to assess the role of cannabinoid CB receptors in memory. Cannabinoid CB1 knock-out mice are able to retain memory for at least 48 h after the first trial whereas the wild-type controls lose their capacity to retain memory after 24 h. These results suggest that endogenous cannabinoid CB receptors play a crucial role in the process of memory storage and retrieval.

Complex pharmacology of natural cannabivoids: Evidence for partial agonist activity of Δ9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors

Delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol are three important natural cannabinoids from the Marijuana plant (Cannabis sativa). Using [35S]GTP-gamma-S binding on rat cerebellar homogenate as an index of cannabinoid receptor activation we show that: delta9-THC does not induce the maximal effect obtained by classical cannabinoid receptor agonists such as CP55940. Moreover at high concentration delta9-THC exhibits antagonist properties. Cannabinol is a weak agonist on rat cerebellar cannabinoid receptors and cannabidiol behaves as an antagonist acting in the micromolar range.

Enzyme-resistant CCK analogs with high affinities for central receptors

Based on the results of the in vitro metabolism of CCK8 by various peptidases, we have synthesized three CCK analogs: Boc-Tyr(SO3H)-Nle-Gly-Trp-(N- Me)Nle-Asp-Phe-NH2 (compound I), Boc-Tyr(SO3H)-gNle-mGly-Trp-Nle-Asp-Phe-Nh2 (compound II), Boc-Tyr(SO3H)-gNle-mGly-Trp-(N-Me)Nle-Asp-Phe-NH2 (compound III). In in vitro enzymatic degradation studies, these compounds showed a high stability toward either enkephalinase or the enzymes present in crude rat brain membranes preparations. Moreover, in binding studies on guinea pig tissues, these CCK-related peptides were characterized by high apparent affinities for brain CCK receptors and by a broader range of affinities for pancreatic CCK receptors. This broad range of affinities was reflected by their pharmacological potencies in the guinea pig pancreatic amylase release and ileum contraction assays. These enzyme-resistant CCK analogs provide therefore valuable tools to investigate the pharmacology of CCK.

Opposite effects of sulfated cholecystokinin on DA-sensitive adenylate cyclase in two areas of the rat nucleus accumbens

The nucleus accumbens of the rat receives a mixed DA/CCK8 innervation in its posterior part while its anterior part is innervated by distinct DA and CCK8 fibres. In vitro, the addition of CCK8 (0.3-1 microM) potentiated the activating effect of DA (10-30 microM) on adenylate cyclase in tissue homogenates obtained from the posterior part of the nucleus accumbens, whilst this activating effect was reduced by CCK8 in the anterior part. These results suggest the existence of two types of regulation of the D1 receptor by CCK8 depending on the identity (mixed or not mixed) of their innervating fibres.

Proteolytical processing of mutated human amyloid precursor protein in transgenic mice.

The evidence that betaA4 is central to the pathology of Alzheimers disease (AD) came from the identification of several missense mutations in the amyloid precursor protein (APP) gene co-segregating with familial AD (FAD). In an attempt to study the proteolytical processing of mutated human APP in vivo, we have created transgenic mice expressing the human APP695 isoform with four FAD-linked mutations. Expression of the transgene was controlled by the promoter of the HMG-CR gene. Human APP is expressed in the brain of transgenic mice as shown by Western blot and immunohistology. The proteolytic processing of human APP in the transgenic mice leads to the generation of C-terminal APP fragments as well as to the release of betaA4. Despite substantial amounts of betaA4 detected in the brain of the transgenic mice, neither signs of Alzheimers disease-related pathology nor related behavioural deficits could be demonstrated.

Synthesis, anticonvulsant and neuroprotective activities of RP 66055, a riluzole derivative

Abstract RP 66055, a riluzole derivative, has been characterized as a potent anticonvulsant and in vivo neuroprotective agent.

Synthesis and pharmacological properties of 5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, a new competitive AMPA/KA receptor antagonist

The excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders. Consequently, excitatory amino acid antagonists may have an important therapeutic potential in the treatment of these diseases. Glutamate interacts with at least three types of receptor: 1) NMDA (N‐methyl‐D‐aspartic acid) receptors; 2) AMPA [2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)propionic acid]/kainic acid (KA) receptors; and 3) metabotropic receptors. Blockade of ionotropic AMPA/KA receptors has been shown to prevent cerebral ischemia insult in experimental models. This article describes the synthesis, pharmacological activity, and neuroprotective properties of 5H,10H‐imidazo[1,2‐a]indeno[1,2‐e]pyrazine‐4‐one (1), a novel AMPA/KA antagonist which showed micromolar affinity at AMPA/KA receptors and competitively inhibited functional responses mediated by these receptors. In mice, 1 had significant anticonvulsive properties and conferred protection against hypobaric hypoxia and KCN intoxication. In rats and gerbils, 1 possesses significant activity in models of global or focal cerebral ischemia, as well as in a model of neurotrauma. Compound 1 was prepared from 2‐bromo‐indanone using two synthetic pathways in two or three steps with moderate (30%) or good (70%) yields, respectively. Drug Dev. Res. 48:121–129, 1999.

App, Apoe, and Presenilin Transgenics

Both environmental and genetic factors are involved in Alzheimer’s Disease (AD) aetiology. Mutations in the amyloid precursor protein (APP) and in presenilin PS1 and PS2 genes cause early-onset forms of the disease while the apolipoprotein ApoEe4 allele is a risk factor for AD (reviewed in Selkoe, 1996; Hardy, 1997). Environmental factors such as trauma and inflammation have also been implicated in the pathology but the overall mechanism of the disease is poorly understood, hampering the development of therapeutic treatments. An animal model of the disease would be of great interest to both unravel the pathophysiological mechanism in vivo and to provide a model for testing of therapeutic approaches. Recently, large overexpression of mutated forms of APP in two transgenic mouse models has been shown to lead to amyloid plaque formation and behavioral deficits (Games et al., 1995; Hsiao et al., 1996). However, mutations in APP and PS’s proteins have also been recently shown to contribute to a similar pathological process, the increase in production of the long form of Aβ (Aβ 1-42, Selkoe, 1996, Duff e

Riluzole Series. Synthesis and in Vivo “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines and 3-Substituted-2-imino-benzothiazolines

Xal., 1996; Borchelt et al., 1996), possibly through a direct physical interaction (Weidemann et al, 1997). Therefore, rather than large overexpression, transgenic models based on a combination of the known genetic factors expressed at more physiological levels could potentially lead to a more suitable model of the disease. Towards that goal, we have generated several human mutant APP, and PS’s transgenic rodent lines and combined them by breeding both together and with ApoE-KO animals.