RESUMO
Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-ß pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.
Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Anticorpos/administração & dosagem , Encéfalo/imunologia , Imunoterapia , Receptor de Morte Celular Programada 1/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Anticorpos/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Interferon gama/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Baço/imunologiaRESUMO
Most antibodies display very low brain exposure due to the blood-brain barrier (BBB) preventing their entry into brain parenchyma. Transferrin receptor (TfR) has been used previously to ferry antibodies to the brain by using different formats of bispecific constructs. Tetravalent bispecific tandem immunoglobulin Gs (IgGs) (TBTIs) containing two paratopes for both TfR and protofibrillar forms of amyloid-beta (Aß) peptide were constructed and shown to display higher brain penetration than the parent anti-Aß antibody. Additional structure-based mutations on the TfR paratopes further increased brain exposure, with maximal enhancement up to 13-fold in wild-type mice and an additional 4-5-fold in transgenic (Tg) mice harboring amyloid plaques, the main target of our amyloid antibody. Parenchymal target engagement of extracellular amyloid plaques was demonstrated using in vivo and ex vivo fluorescence imaging as well as histological methods. The best candidates were selected for a chronic study in an amyloid precursor protein (APP) Tg mouse model showing efficacy at reducing brain amyloid load at a lower dose than the corresponding monospecific antibody. TBTIs represent a promising format for enhancing IgG brain penetration using a symmetrical construct and keeping bivalency of the payload antibody.
RESUMO
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aß25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aß25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
Assuntos
Agressão/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
Assuntos
Amidoidrolases/antagonistas & inibidores , Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Agonistas de Receptores de Canabinoides/metabolismo , Carbamatos/farmacologia , Dioxanos/farmacologia , Inibidores Enzimáticos/farmacologia , Receptores de Canabinoides/genética , Estresse Psicológico/tratamento farmacológico , Doença Aguda , Amidas , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Ansiolíticos/síntese química , Transtornos de Ansiedade/fisiopatologia , Ácidos Araquidônicos/metabolismo , Carbamatos/síntese química , Doença Crônica , Dioxanos/síntese química , Endocanabinoides/metabolismo , Inibidores Enzimáticos/síntese química , Etanolaminas/metabolismo , Feminino , Expressão Gênica , Masculino , Camundongos , Ácidos Oleicos/metabolismo , Ácidos Palmíticos/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Ratos Sprague-Dawley , Receptores de Canabinoides/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
INTRODUCTION: Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. METHODS: We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22). RESULTS: SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. DISCUSSION: Long-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.
RESUMO
Lithium chloride (LiCl) and morphine both produce a conditioned taste avoidance response, while only LiCl is able to elicit a conditioned rejection response (taste reactivity), indicating that the effects of conditioning are drug and preparation dependent. The present experiments extend this assessment to another behavioral preparation, schedule-induced polydipsia (SIP), by examining the ability of LiCl and morphine to produce conditioned suppression of nonregulatory drinking. In Experiment 1, schedule-induced saccharin consumption was followed by LiCl or morphine (at doses comparably effective in conditioning taste avoidance under water deprivation) or by the distilled water vehicle. Although both LiCl and morphine suppressed SIP, morphine produced a significantly weaker suppression than did LiCl. Using a massed feeding design in which animals received all their food pellets in a single meal, Experiment 2 determined that LiCl and morphine were equally effective in suppressing consumption, indicating that the differential effects seen under SIP were due to the schedule of spaced food pellet deliveries. The basis for the differential effects of LiCl and morphine on SIP may be a function of an increase in the reinforcing properties of drugs of abuse (such as morphine) within this procedure that mask the acquisition and/or display of the conditioned suppression. If so, then this procedure may be useful in assessing the reinforcing properties of such drugs.
Assuntos
Comportamento de Ingestão de Líquido/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Morfina/farmacologia , Esquema de Reforço , Animais , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Ratos , Ratos Sprague-Dawley , Sacarina/administração & dosagemRESUMO
Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
Assuntos
Analgésicos/farmacologia , Ácidos Araquidônicos/metabolismo , Carbamatos/farmacologia , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Aprendizagem/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Monoacilglicerol Lipases/metabolismo , Sulfonamidas/farmacologia , Acetilcolina/metabolismo , Administração Oral , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Ácidos Araquidônicos/química , Sítios de Ligação , Encéfalo/metabolismo , Antagonistas de Receptores de Canabinoides/farmacologia , Carbamatos/química , Carbamatos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Modelos Animais de Doenças , Estimulação Elétrica , Endocanabinoides/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicerídeos/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Hidrólise , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Monoacilglicerol Lipases/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/patologia , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Pirazóis/farmacologia , Rimonabanto , Convulsões/tratamento farmacológico , Convulsões/patologia , Sulfonamidas/química , Sulfonamidas/uso terapêuticoRESUMO
SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment ß25â35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.