“New cannabis-based treatments could improve memory loss in Alzheimer’s sufferers, scientists claim.
One of the 400 compounds in the drug can significantly slow memory problems caused by the disease, tests show.”
Monthly Archives: January 2013
Current and future therapy in Alzheimer’s disease.
Abstract
“Dementia is increasingly being recognized as one of the most important medical problems in the elderly. As most pharmacological research within the field of dementia is focused on Alzheimer’s dementia (AD), this review will focus on pharmacological interventions in AD. Most disease-modifying therapies are based on the amyloid hypothesis. In this hypothesis, the pathological accumulation of Abeta in the brain leads to oxidative stress, neuronal destruction and finally the clinical syndrome of AD. Following this hypothesis, secondary prevention of AD can be made by: decreasing the production of Abeta, stimulation of clearance of Abeta formed or prevention of aggregation of Abeta into amyloid plaques. First a short overview on current approved therapies for AD is given. The main part of the review will focus on potential disease-modifying therapies for AD that are currently being studied in phase I to phase III trials.”
[Therapy of Alzheimer disease].
Abstract
“Dementia is one of the most important health problems in the aging populations. The most frequent cause of it is Alzheimer’s disease (AD) which is characterized by intracellular neuro-fibrillary tangles (NFT) and the extracellular senile plaques. The NFTs are mainly formed by the hyperphosphorylated microtubule-binding protein, the tau, while the senile plaques are composed of beta-amyloid protein cleaved from the amyloid precursor protein (APP) by the beta- and gamma-secretases. The pharmacotherapy of AD consists of symptomatic and disease-modifying therapies. The most frequently used therapeutic agents are the nootropic drugs supported by personal rather evidence based experiences. The leading-edge therapy of AD at present is the inhibition of the acetylcholine-esterase enzyme (AChEI) with mainly cognitive symptomatic and weak disease-modifying effects; they are licensed in the mild and middle stages of AD (MMSE 26-10), but their effect is proved in the severe stage of the disease and they are effective in the management of the neuropsychiatric symptoms too. Memantine (which is an inhibitor of the N-metil-D-aspartate receptor) is used in the middle and severe stages of AD and it can be effectively combined with AChEIs. The future therapy of AD will possibly be a “causative” therapy. The most frequent directions are therapies aiming to decrease the production or the deposition of beta-amyloid peptide. The active vaccination study of AN-1792 was terminated because of immunological side-effects, but several active and passive immunisation therapies are in development nowadays. It is also possible to inhibit the aggregation of the beta-amyloid peptide with peptide fragments or with Cu2+ and Zn2+ ion chelators. A promising direction is the inhibition of the enzymes responsible for the production of the beta-amyloid peptide: beta-secretase inhibitors with low molecular weight and penetrability through the blood-brain barrier are developed while the inhibitors of the gamma-secretase (some of them are the derivatives of the non-steroid anti-inflammatory drug ibuprofen) are tested in phase III trials. The inhibition of NFT formation might be promising too and inhibitors of the enzymes responsible for the hyperphosphorylation of the tau (like the glycogen synthase kinase-3) are in develo ment. Several other therapeutic methods are studied. NSAIDs and statins are useful in the prevention of the disease but they are failed in symptomatic treatment. There are promising studies in few patients using nerve growth factor therapy and some studies proved that peroxisome proliferator activated receptor (PPAR) agonist rosiglitazone (which is used to the treat diabetes mellitus) is effective in AD. The presently modest therapeutic interventions of AD will explode in the near future and together with the improved diagnostics of the disease they will cause further specialization with increased treatment and caring costs amplified by the ever growing number of the patients. This means that AD is and will be one of the most important diseases for the health care systems.”
New pathways in drug discovery for Alzheimer’s disease.
Abstract
“Specific treatments for Alzheimer’s disease (AD) were first introduced in the 1990s using the acetyl-cholinesterase inhibitors. More recently, the N-methyl-D-aspartate (NMDA) antagonist memantine has become available. Although these treatments do provide a modest improvement in the cognitive abnormalities present in AD, their pharmacology is based on manipulation of neurotransmitter systems, and there is no compelling evidence that they interfere with the underlying pathogenic process. Pathologic and genetic data have led to the hypothesis that a peptide called amyloid ss(Abeta) plays a primary role in the pathophysiology of AD. Several investigational therapies targeting Abeta are now undergoing clinical trials. This paper reviews the available data regarding Abeta-directed therapies that are in the clinic and summarizes the approach to biomarkers and clinical trial designs that can provide evidence of modification of the underlying disease process.”
Cannabinoid CB1 receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B up-regulation in vitro.
“…the involvement of the endocannabinoid system was investigated by using selective inhibitors of endocannabinoid inactivation (cellular re-uptake or enzymatic hydrolysis) and selective cannabinoid CB1 and CB2 receptor antagonists and by silencing the CB1 receptor…
Our data suggest that selective activation of CB1 receptors by either exogenous or endogenous cannabinoids might afford neuroprotection…”
CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice.
“The present study shows that chronic administration of the cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards…
… targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer’s disease.”
Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro.
“Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer’s protein, β-amyloid (Aβ)…
…the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation…protective effect of cannabidiol against oxidative stress…
…divergent pathways for neuroprotection of these two cannabinoids.”
Protective effect of cannabinoid CB1 receptor activation against altered intrinsic repetitive firing properties induced by Aβ neurotoxicity.
“The amyloid β (Aβ) protein is believed to be the key pathological mediator of Alzheimer’s disease (AD) which is the first and most well known type of dementia. Despite a growing body of evidence indicating that Aβ neurotoxicity induces changes in synaptic function, little effort, if any, has been made to investigate the effect of in vivo Aβ treatment on intrinsic neuronal properties. The present study was designed to examine the effects that in vivo Aβ treatment have on the intrinsic repetitive firing properties of CA1 pyramidal neurons, using whole cell patch clamp recording. Protective effect of cannabinoid CB1 receptor activation was also investigated against Aβ-induced alterations in evoked electrophysiological activities. The findings from present study demonstrated that a bilateral injection of Aβ into the prefrontal cortex causes robust changes in activity-dependent electrophysiological responses in hippocampal CA1 pyramidal neurons. The effects of Aβ treatment alone was almost completely prevented by combined treatment with Aβ and ACEA, a selective CB1 receptor agonist. It can be concluded Aβ treatment reduces evoked neuronal activity and activation of CB1 cannabinoid receptors may have beneficial preventative effects on Aβ-induced electrophysiological changes.”
http://www.ncbi.nlm.nih.gov/pubmed/22172925
https://www.sciencedirect.com/science/article/abs/pii/S0304394011015667
CB1 cannabinoid receptor activation rescues amyloid β-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal CA1 pyramidal neurones.
“Amyloid beta (Aβ) is believed to be responsible for the synaptic failure that occurs in Alzheimer’s disease (AD), but there is little known about the functional impact of Aβ on intrinsic neuronal properties. Here, the cellular effect of Aβ-induced neurotoxicity on the electrophysiological properties of CA1 pyramidal neurons and the mechanism(s) of neuroprotection by CB1 cannabinoid receptor activation was explored.
CONCLUSIONS:
In vivo Aβ treatment altered significantly the intrinsic electrophysiological properties of CA1 pyramidal neurons and the activation of CB1 cannabinoid receptors exerted a strong neuroprotective action against Aβ toxicity.”
Distribution patterns of cannabinoid CB1 receptors in the hippocampus of APPswe/PS1ΔE9 double transgenic mice.
Abstract
“Cannabinoids have neuroprotective effects that are exerted primarily through cannabinoid CB1 receptors in the brain. This study characterized CB1 receptor distribution in the double transgenic (dtg) APP(swe)/PS1(ΔE9) mouse model for Alzheimer’s disease. Immunohistochemical labeling of CB1 protein in non-transgenic mice revealed that CB1 was highly expressed in the hippocampus, with the greatest density of CB1 protein observed in the combined hippocampal subregions CA2 and CA3 (CA2/3). CB1 immunoreactivity in the CA1 and CA2/3 hippocampal regions was significantly decreased in the dtg APP(swe)/PS1(ΔE9) mice compared to non-transgenic littermates. Reduced CB1 expression in dtg APP(swe)/PS1(ΔE9) mice was associated with astroglial proliferation and elevated expression of the cytokines inducible nitric oxide synthase and tumor necrosis factor alpha. This finding suggests an anti-inflammatory effect of cannabinoids that is mediated by CB1 receptor, particularly in the CA2/3 region of the hippocampus. Furthermore, the study suggests a decreased CB1 receptor expression may result in diminished anti-inflammatory processes, exacerbating the neuropathology associated with Alzheimer’s disease.”