A chronic low dose of [Delta]9-tetrahydrocannabinol (THC) restores cognitive function in old mice : Nature Medicine : Nature Research

Cannabis sativa plant (Photo credit: Wikipedia)

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging1, 2. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals3, 4, 5 and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower6. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments."



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Activation of CB2 Receptor System Reverses Amyloid-Induced Memory Deficiency and Restores SOX2 Activity in a Transgenic Mouse Model of Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The brains of patients with AD are characterized by extensive deposits of extracellular aggregation of amyloid-beta peptides. These peptides form senile plaques and intracellular aggregation of hyperphosphorylated tau protein. In addition, amyloid fibrils activate the inflammatory pathway, characterized by the activated microglia and astrocytes seen in the brains of patients with AD.

Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in AD. CB2 receptors are upregulated in reactive microglial cells in AD. This upregulation of CB2 receptors tends to attenuate the activation of early pro-inflammatory microglial signaling pathways associated with AD.

Sox2 (sex-determining region Y (SRY)-box 2) is a transcriptional factor that is essential for maintaining self-renewal/proliferation of undifferentiated embryonic stem cells (ESCs) and multipotency of neural stem cells (NSCs). Sox2 behaves as a protective factor during the development of Alzheimer’s disease.

We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl) piperidine (MDA7) a novel, blood brain barrier-permeant, and highly selective CB2 agonist that lacks psychoactivity on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment in the Tg-APPsw/PSEN1DE9 (APP/PS1) mouse model of AD. APP/PS1 mice are well suited for our investigations because they exhibit high production of Aβ peptides in the brain, accumulation of amyloid plaques, and demonstrate cognitive impairments. Senile plaques can be detected by thioflavin S or 3D6 as early as 4 months of age, and there is an overall increase in plaque burden with age. PAPP/PS1 mice displayed significantly impaired glutamatergic long-term potentiation (LTP) in the hippocampal CA1 neurons, indicating an impaired synaptic plasticity. LTP is an experimental phenomenon that takes place at excitatory glutamatergic synapses and is believed to play a central role in learning and memory.

At 3 mo of age, MDA7 14 mg/kg was administered intraperitoneally (i.p.) every other day for 5 mo. Another cohort of APP/PS1 received i.p. injections of the vehicle at alternate days for 5 mo. In the APP/PS1 transgenic mice, compared to wild type mice, treatment with MDA7 (i) ameliorated the expression of Iba1 (microglia marker), (ii) promoted amyloid-beta clearance in the hippocampal CA1, (iii) restored the expression of SOX2 (stem cell marker) in the hippocampal dentate gyrus, and (iv) restored synaptic plasticity, cognition and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for Alzheimer’s disease.

Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.

Direct acting antivirals have significantly improved treatment outcomes
in chronic hepatitis C (CHC), but side effects, drug resistance and cost
mean that better treatments are still needed. Lipid metabolism is
closely linked with hepatitis C virus (HCV) replication and
endocannabinoids are major regulators of lipid homeostasis. The
cannabinoid 1 (CB1) receptor mediates these effects in the liver. We
have previously shown up-regulation of CB1 receptors in the livers of
patients with CHC, and in a HCV cell culture model. Here we investigated
whether CB1 blockade inhibits HCV replication. The antiviral effect of a
CB1 antagonist, AM251 was examined in the JFH1 cell culture and
subgenomic replicon models. The effects on the expression of genes
involved in lipid metabolism were also measured. CB1 shRNA was used to
confirm that the effects were specific for the cannabinoid receptor.
Treatment with AM251 strongly inhibited HCV RNA (~70%), viral protein
(~80%), the production of new virus particles (~70%), and virus
infectivity (~90%). As expected, AM251 reduced the expression of
pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes
promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by
AMPK. Stable CB1 knockdown of cells infected with HCV showed reduced
levels of HCV RNA, compared with controls. Reduced CB1 signalling
inhibits HCV replication using either pharmacological inhibitors or CB1
shRNA. This may be due, at least in part, to reduced lipogenesis,
mediated by AMPK activation. We suggest that CB1 antagonists may
represent an entirely new class of drugs with activity against HCV.

Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [18F]MK-9470.

Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. While the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [18F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at post-natal days (PND) 32-42 (adolescence) and in the same animals again at PND 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative standard uptake (rSUV) values compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies.

Prospects for cannabinoid therapies in viral encephalitis.

 Cannabinoids are promising therapies to support neurogenesis and decelerate disease progression in neuroinflammatory and degenerative disorders. Whether neuroprotective effects of cannabinoids are sustainable during persistent viral infection of the CNS is not known. Using a rodent model of chronic viral encephalitis based on Borna Disease (BD) virus, in which 1 week treatment with the general cannabinoid WIN 55,212-2 has been shown to be neuroprotective (Solbrig et al., 2010), we examine longer term (2 week treatment) effects of a general (CB1 and CB2) cannabinoid receptor agonist WIN55,212-2 (1mg/kg ip twice per day) or a specific (CB2) cannabinoid receptor agonist HU-308 (5mg/kg ip once daily) on histopathology, measures of frontostriatal neurogenesis and gliogenesis, and viral load. We find WIN and HU-308 differ in their ability to protect new BrdU+cells. The selective CB2 agonist HU increases BrdU+ cells in prefrontal cortex (PFC), significantly increases BrdU+ cells in striatum, differentially regulates polydendrocytes vs microglia/macrophages, and reduces immune activation at a time WIN-treated rats appear tolerant to the anti-inflammatory effect of their cannabinoid treatment. WIN and HU had little direct viral effect in PFC and striatum, yet reduced viral signal in hippocampus. Thus, HU-308 action on CB2 receptors, receptors known to be renewed during microglia proliferation and action, is a nontolerizing mechanism of controlling CNS inflammation during viral encephalitis by reducing microglia activation, as well as partially limiting viral infection, and uses a nonpsychotropic cannabinoid agonist.

Endocannabinoids trigger inflammation that leads to diabetes

The researchers demonstrated that endocannabinoid activation of macrophages in the pancreas leads to activation of a protein complex within macrophages called the Nlrp3 inflammasome.  The inflammasome, in turn, releases molecules that cause the death of pancreatic beta cells and the progression of type 2 diabetes in the rats.

Compounds That Stimulate The Cannabinoid Type 2 Receptor In White Blood Cells Can Weaken HIV-1 Infection

MNT "A new use for compounds related in composition to the active ingredient in marijuana may be on the horizon: a new research report published in the Journal of Leukocyte Biology shows that compounds that stimulate the cannabinoid type 2 (CB2) receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection. The CB2 receptor is one of the  the molecular links through which the pharmaceutical properties of cannabis are manifested. "

Potential cannabinoid drug for treatement of Alzheimer's disease investigated

In a study published online in theNeurobiology of Aging, the compound MDA7, a CB2 cannabinoid receptor agonist, induced beneficial immune  responses that limited the development of Alzheimer's disease. Treatment with the compound restored cognition, memory and synaptic plasticity -- a key neurological foundation of learning and memory -- in an animal model.