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Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca(2+) activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections.
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Pharmaceuticals 2010, 3, 1873-1886; doi:10.3390/ph3061873
ISSN 1424-8247
Cannabinoids and Viral Infections
Carol Shoshkes Reiss
Department of Biology, Center for Neural Science, NYU Cancer Institute and Department of
Microbiology, New York University, 100 Washington Square East, New York, NY, 10003, USA;
E-Mail:; Tel.: +1-212-998-8269; Fax: +1-212-995-4015
Received: 21 May 2010; in revised form: 28 May 2010 / Accepted: 9 June 2010 /
Published: 9 June 2010
Abstract: Exogenous cannabinoids or receptor antagonists may influence many cellular
and systemic host responses. The anti-inflammatory activity of cannabinoids may
compromise host inflammatory responses to acute viral infections, but may be beneficial in
persistent infections. In neurons, where innate antiviral/pro-resolution responses include
the activation of NOS-1, inhibition of Ca
activity by cannabinoids, increased viral
replication and disease. This review examines the effect(s) of cannabinoids and their
antagonists in viral infections.
Keywords: pathogens; virus infection; immunomodulation; inflammation
1. Introduction
Both endogenous and exogenous cannabinoids can influence the course of infections in vitro and in
vivo. This review will focus on viral infections of mammals, but will also describe what is known
about other infections. Readers are directed to the excellent accompanying reviews in this issue which
expertly discuss the clinical trials, cell biology, mechanisms of action, impact on inflammation, clinical
applications, and so forth.
Cannabinoids may act either through the CB
or the CB
receptor, which are found on distinct cell
types. The CB
receptor is found on neurons as well as some astrocytes and skeletal muscle cells;
neurons are frequently the target of viral infection. Engagement of the CB
receptor by its endogenous
or exogenous agonists may inhibit the release of Ca
from intracellular or extracellular stores. Since
many important intracellular proteins are Ca
-dependent for activation, signal transduction through
the CB
receptor may impair these secondary pathways and have a profound influence on the ability of
viruses to replicate in neurons.
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In contrast, the response of cells expressing the CB
receptor may influence not only the responses
in that cell, but may alter the course of the host innate and adaptive immune response to the pathogen,
suppressing inflammation and the development of virus-specific cellular and humoral responses. The
outcome on the viral infection will depend on whether inflammation is beneficial or pathogenic in the
specific case.
2. Discussion
When a host is infected with a virus, there is a dynamic competition between the ability of the host
to first marshal innate (hours to days) and then adaptive immunity (>7 days post infection) vs. the
replication and spread of the virus first within the host and then to additional susceptible individuals.
When a virus is able to out-pace the containment efforts, the host may succumb. Pathology may result
from damage to tissues by viral-induced cellular apoptosis or necrosis, or alternatively, host immune
responses may result in immunopathology or the perceived symptoms of the infection. If, however,
innate and adaptive immunity successfully suppress viral replication, specific life-long immunity
may result.
In order to understand the influences on the host response which may be the result of cannabinoids,
it is important to examine some of the cellular pathways which are dependent on Ca
enzymes. Table 1 indicates some of the well characterized pathways involved and their potential
impact on viral infections.
The common recurring impact of Ca
-dependent enzymes is a role in inflammation. This ranges
from regulation of many signal transduction pathways, production of pro-inflammatory and
pro-resolving lipid mediators downstream of arachidonic acid, to activation of Nitric Oxide Synthase
and the production of reactive nitrogen intermediates, to proteolytic enzymes which remodel the
cytoskeleton or extracellular matrix, and apoptosis.
Inflammation is essential for recruitment of both innate and adaptive immune cells to the site of
infection to control virus production and limit spread, and then to promote recovery. Inflammation is
comprised not only of non-specific cells (sequentially these are polymorphonuclear leukocytes, natural
killer cells, macrophages) and then pathogen-specific T lymphocytes recruited from circulation, and
activation of antibody-secreting B lymphocytes, but also induction of production and secretion of
cytokines, chemokines, interferons, complement components, acute phase reactants, reactive oxygen
and nitrogen intermediates, and other mediators [24–26]. Readers are referred to the accompanying
review by Bani, Mannaioni, Passani, and Masini [27]. Thus, many of these critical pathways may be
impaired or compromised when endogenous or exogenous cannabinoids are present during an
infection [28].
Cannabinoids have been used both recreationally by groups of people who have viral infections, and
experimentally by scientists investigating their impact in vitro or in animal models. Table 2 presents
what has been published about these populations in peer reviewed journals. In most of the infections
studied (Table 2), it is apparent that cannabinoid treatment, whether in vitro or in vivo, had profound
impact on the virus-host (cell) interactions. For HSV-2, HIV-1, KSHV, influenza and VSV viral
replication, or surrogate measures of infection, were found to be substantially increased upon
cannabinoid treatment [30,34,39,50,52,63]. In HIV-1 infection, syncytia formation was enhanced, and
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monocytes were stickier on endothelial cells [57,58]. In one study, KHSV was more likely to exit
latency and enter lytic infection when transformed cells were treated with THC [39], however, another
study found the opposite result in several herpesvirus infections [38].
Table 1. Some Ca
-dependent enzymes which may be inhibited by Cannabinoids and
speculated role in host responses relevant for viral infections.
Role(s) in viral
cPhospholipase A
Arachidonic acid metabolites (prostaglandins,
leukotrienes, lipoxins, resolvins) and
[1,2] Inflammation and its
Phospholipase C
- Receptor-mediated tyrosine
Production of Inositol 1,4,5-triphosphate from
[3] Signal transduction
Phospholipase D
Exocytosis in neuroendocrine cells [4] Neurotransmission
Calcineurin Activation of NFAT—gene expression [5,6] Signal transduction
- Nitric oxide synthase-1
- Nitric oxide synthase-3
Conversion of argenine to NO in neurons and
endothelial cells; production of ONOO-, -SNO,
Inhibition of viral infection
Anti-viral; NO
decoration of viral
proteins; capillary
dilation; inflammation
-Calmodulin dependent
protein kinases
- CaMKK activation of
Wnt-2-dependent dendrite growth &
Energy, epithelial cell polarity
T cell activation
[13–17] Adaptive immune
Calpains [Ca
Neutral proteases [many tissues]
Cell membrane fusion, synaptic remodeling,
activating PKC, remodeling cytoskeleton,
transcription factors
[18–20] Cytoskeletal plasticity,
cell migration,
Matrix metalloproteinases Extracellular matrix remodeling, inflammation [21] Inflammation
Calpastatin Cell fusion in fertilization [22] Formation of
/giant cells
Transglutaminases Cross-linking/deamination of proteins –wound
healing, tissue repair, apoptosis, cell cycle
control, inflammation and fibrosis
[23] Inflammation, fibrosis,
cell cycle and
programmed cell death
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Table 2. Cannabinoids and Viral Infections.
In vivo
In vitro
Agonist /
Comments Ref.
L. monocyto-
In vivo Δ9-THC decreased
resistance to
systemic infection [29]
HSV-2 In vivo Δ9-THC increased
severity of
lesions &
delayed onset of
DTH response
vaginal model
HSV-2 In vivo Δ9-THC decreased Type I
IFN response
i.v. infection [31]
HSV-2 In vivo Δ9-THC decreased
resistance to
severity of
vaginal guinea pig
HSV-1,-2 In
Δ9-THC failed to
antiviral effect in
human & monkey
HSV-2 In
Δ9-THC 100-fold
increase in
Vero cells,
increased CPE
HSV-2 both Δ9-THC decreased T cell
immunized then T
cells cultured
Δ9-THC decreased
in TC
virus incubated
with THC
HSV-1 both Δ9-THC decreased CD8
CTL activity
C3H mice
immunized, L929
In vivo Δ9-THC Immediate
early ORF
from latency
latently infected B
cells in tissue
KSHV In vivo Δ9-THC increased
viral load
efficiency of
activation of
lytic switch
transformation of
endothelial cells
primary human
microvascular cells
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Table 2. Cont.
In vivo
In vitro
Agonist /
Comments Ref.
Cowpox In vivo Marijuana
weak Ab
production, no
neutralizing Abs
Case report [40]
Anandamide decreased release
of NO2- and
NO is antiviral for
Anandamide increased IL-6
astrocyte culture
B6 and SJL mice
TMEV In vivo WIN-55,212 ameliorates
progression of
disease TMEV-
decreased DTH,
decreased IL-1,
IL-6, IFN-
γ , TNF-α,
mouse model of
TMEV In vivo OMDM1,
decreased MHC
II, inhibited
NOS-2, reduced
proposed MS
therapy with
role of CB
receptors in
reduced IL-
12p40, reduced
WIN-55,212 CB
increased vs.
role of PI3 kinase
pathway in CB
but MAPK for
TMEV signaling
proposed role on
blood-flow and
immune activity
TMEV In vivo Palmitoyl-
reduction in
motor disability
TMEV both WIN-55,212 inhibited ICAM
& VCAM on
role for PPAR-γ
receptors in
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Table 2. Cont.
In vivo
In vitro
Agonist /
Comments Ref.
Influenza In vivo Δ9-THC HA mRNA
metaplasia of
mucous cell
decreased CD4,
CD8, and
Influenza In vivo Δ9-THC HA mRNA
decreased in
pathology +/-
KO mice had
increased CD4
and IFN-γ
KO mice [51]
VSV In vitro WIN-55,212 increased
viral titers
decreased NOS-
1 activity
antagonized IFN-
antiviral pathway
suggested disease
progression likely
in neurons/viral
BDV In vivo WIN-55,212 protected BrdU-
positive neural
progenitor cells
in striatum
suggested treatment
of encephalitis with
inflammation and
HCV In vivo Marijuana
progression of
liver fibrosis
HCV In vivo Oral
no viral markers
or immune
markers studied
7 week clinical trial
for anorexia and
HCV In vivo Marijuana
progression of
liver fibrosis;
disease severity
pathological survey
of 204 HCV
HIV-1 In vitro Δ9-THC, CP-
55,940, WIN-
increased syn-
cytia formation
MT-2 cells
& CB
enhance HIV-1
HIV-1 In vitro anandamide increased
adherence for
uncoupled NO
release, inhibited
human saphenous
vein or internal
thoracic artery;
speculate higher
titers in vivo
HIV-1 Tat In vitro WIN-55,212 reduced tat-
inhibited NOS-2
C6 rat glioma cell
HIV-1 In vivo Marijuana
numbers of
3 week trial [60]
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Table 2. Cont.
In vivo
In vitro
Agonist /
Comments Ref.
HIV-1 In vivo Marijuana
CD4+ and CD8+
cells unchanged
3 week trial,
HIV-1 WIN-55,212 inhibited
CD4 and microglial
HIV-1 In vivo THC increased
decreased CD4
cells, increased
scid-Hu mouse
inhibited Ca
substance P,
model of BBB, co-
culture of Human
brain microvascular
endothelial cells
and astrocytes
HIV-1 In vivo WIN-55,212 dose-related
hypothermia in
mouse pre-optic
WIN-55,212 is
antagonist for
mouse model for
ulation by direct
injection of WIN-
55,212 to brain
POAH center
HIV-1 Tat In
inhibition of
U937 migration
to Tat
possible anti-
U937 cells in
Legend: BDV, Borna disease virus; EBV, Epstein-Barr virus; HCV, Hepatitis C virus; HIV, Human
immunodeficiency virus; HSV, Herpes simplex virus; HVS, Herpes virus samirii; KO, knock-out mice;
KSHV, Kaposi's sarcoma herpes virus; L. monocytogenes, Listeria monocytogenes; MHV-68, Murine herpes
virus-68; TMEV, Theiler's murine encephalomyelitis virus; VSV, Vesicular stomatitis virus.
Disease was more severe in HSV-2-infected guinea pigs which were treated with THC [29,30,32].
In HCV infections, clinical studies have shown a profound co-morbidity of recreational cannabinoid
use, for disease progression [54,56]. One case report of Cowpox infection, a very rare human pathogen,
indicated that recreational use of cannabinoids was associated with generalized infection and very poor
immune responses to the virus [40].
In contrast, in those infections where host inflammatory responses are often associated with
pathology, and not with clearance and recovery, cannabinoid treatment of hosts was beneficial. These
included one mouse model of multiple sclerosis, the Theiler's murine encephalomyelocarditis virus
(TMEV)-induced demyelinating disease (IDD), where progression towards the paralysis and disability
were ameliorated [44,45,48] and in Borna disease virus (BDV) where neural progenitors were
protected from proinflammatory cytokine-mediated damage [53] infections. TMEV-IDD is
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characterized by microglial activation in the spinal cord of mice and a T cell-mediated autoimmune
demyelinating disease, triggered by the viral infection [42,67–69]. Persistent BDV infection of the
central nervous system is associated with immunopathology associate with inflammation and
production of pro-inflammatory cytokines, induction of NOS-2 in microglia, and breakdown of the
blood-brain barrier [70–73]. In both BVD and TMEV-IDD, the targets for the anti-inflammatory
effects of the cannabinoid treatment are lymphocytes and mononuclear cells.
Two excellent reviews of the impact of cannabinoids on bacterial, yeast, and protozoan infections
were published in the same issue of Journal of Neuroimmunology [26,74]. These infections included
Treponema pallidum (Syphilis), Legonella pneumophila (Legionnaires' disease), Staphylococci aureus
and S. albus, Listeria monocytogenes, Candida albicans (Thrush), and Naegleria fowleri. Both reviews
concluded that THC significantly reduced host resistance to infection of experimental animals, and
speculated that similar host compromise would be found in man. In the more than 12 years since those
reviews were published, additional findings have extended the serious consequences of cannabinoids
on host responses to pathogens and opportunistic infections. Marijuana use is a risk factor for
Mycobacterium tuberculosis (TB) infections [75–77]; this author speculates the suppression of host
innate immune responses by THC contributes to the increased severity of TB in users. Similarly, more
serious exacerbations central nervous system infection by Acanthamoeba among HIV-infected patients
has been attributed to marijuana consumption [78], possibly by inhibiting macrophage chemotaxis [79].
However, the antiinflammatory effects of cannabinoids have been found to be beneficial in attenuating
fever induced by bacterial endotoxin [65,80], inhibiting cytokine responses to Corynebacterium
parvum endotoxin [81]. These drugs may also offer therapeutic efficacy in meningitis caused by
Streptococcus pneumoniae [82] and in irritable bowel syndrome [83,84].
Cannabinoids may relieve pain and may induce hyperphagia, which could be beneficial in
cancer [85,86]. However, these physiological characteristics are not relevant to most viral, bacterial
fungal or parasitic infections, where the regulation of inflammation is central to controlling pathogen
replication and immunopathology. However, the same anti-inflammatory properties of cannabinoids
just described are detrimental to the host in handling the other infections. In most cases, a rapid and
robust inflammatory response, associated with production of proinflammatory cytokines and effect T
lymphocytes capable of eliminating infected cells is essential to recovery and survival.
3. Conclusions
Cannabinoids are profoundly anti-inflammatory and impair many Ca
-dependent enzyme systems
which are central to inflammatory and cell-autonomous antiviral responses. When viral-induced host
responses lead to immunopathology, as is seen in a rodent model of multiple sclerosis, TMEV-IDD, or
in a persistent infection of the central nervous system caused by a non-lytic virus, BDV, cannabinoid
treatment was beneficial.
In all other virus infections, both in vitro and in vivo, cannabinoid treatment led to disease
progression, increased pathology, and sometimes to host death. Therefore, in many clinical settings,
including latent infections caused by HIV-1 or HSV-1, and persistent infection of the liver caused by
HCV, cannabinoids lead to worsened disease outcome.
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The generous support of the U.S. National Institutes of Health, both grants DC039746 and
NS039746, enabled my lab to perform these studies, and to summarize the work of many other labs.
Two former students, Ramon Antonio Herrera and Joseph H. Oved, contributed published [52] and
unpublished data, provided stimulating discussions and critically read this manuscript.
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... Because of the involvement of the ECS in the regulation of oxidative stress and inflammation, endocannabinoids, by activating CB1/2 receptors, influence the course of viral infections. It has been found that induction of CB1 receptors during viral infections in neuronal cells can activate the ERKphosphorylating MAPK cascade and reduce Ca2 + ion concentrations in cells, which lowers nitric oxide (NO) production and pro-inflammatory mediators, which are essential for the development of host responses to viral infections (Reiss, 2010). It has also been suggested that endocannabinoids and CB1 receptors are part of a pathway involved in the development of hepatocyte glucose metabolism disorders due to HCV infection (Sun et al., 2014). ...
... On the other hand, because the CB2 receptor is present in large amounts in immune cells, activation of CB2 receptors exerts a protective effect by suppressing inflammation, oxidative stress, and beneficial regulation of the immune system to viral and bacterial infections (Rom and Persidsky, 2013;He et al., 2019). Moreover, it is believed that, in most cases, activation of cannabinoid receptors increases the progression of infectious diseases by modulating the host's immune response (Reiss, 2010). In viral infections in which the host's inflammatory response is immunopathogenic, activation of the receptors is beneficial for the control of disease development, progression, and pathology (Reiss, 2010). ...
... Moreover, it is believed that, in most cases, activation of cannabinoid receptors increases the progression of infectious diseases by modulating the host's immune response (Reiss, 2010). In viral infections in which the host's inflammatory response is immunopathogenic, activation of the receptors is beneficial for the control of disease development, progression, and pathology (Reiss, 2010). Activation of CB2 receptors also involves the modulation of numerous immune, inflammatory, and redox signaling pathways such as SIRT1/PGC-1a, AMPK/ CREB, MAPK/ERK, and Nrf2/Keap1/HO-1 (Correa et al., 2009;Hashiesh et al., 2020). ...
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One of the growing global health problems are vector-borne diseases, including tick-borne diseases. The most common tick-borne diseases include Lyme disease, tick-borne encephalitis, human granulocytic anaplasmosis, and babesiosis. Taking into account the metabolic effects in the patient’s body, tick-borne diseases are a significant problem from an epidemiological and clinical point of view. Inflammation and oxidative stress are key elements in the pathogenesis of infectious diseases, including tick-borne diseases. In consequence, this leads to oxidative modifications of the structure and function of phospholipids and proteins and results in qualitative and quantitative changes at the level of lipid mediators arising in both reactive oxygen species (ROS) and ROS enzyme–dependent reactions. These types of metabolic modifications affect the functioning of the cells and the host organism. Therefore, links between the severity of the disease state and redox imbalance and the level of phospholipid metabolites are being searched, hoping to find unambiguous diagnostic biomarkers. Assessment of molecular effects of oxidative stress may also enable the monitoring of the disease process and treatment efficacy.
... For example, one unique human network is associated with negative regulation of leukocyte activation with immune response-suppressing MHC class I HLA-G, and another unique human network is involved in 5′-nucleotidase functionality and viral infectivity that promote NEXT-Exosome and endocannabinoid signaling function. The modulation of the airway response, increase of viral load, and attenuation of macrophages and CD4/CD8 T cells by  9 -tetrahydrocannabinol have been well studied (49,50). It seems that influenza may also attenuate the host immune response via this particular signaling pathway. ...
... Mice were anesthetized by intraperitoneal injection of a mixture of ketamine and xylazine (100 and 5 g per gram of body weight), before intranasal administration of either PBS or 100 mol of PPMO mix (50 mol of PPMO1 and PPMO2 each) in 40 l of PBS, on day −2 and day −1. On day 0, mice were challenged intranasally with 40 PFU of PR8 IAV [LD 50 (median lethal dose) = 50 PFU] in 40 l of PBS. Mice were monitored daily for weight loss and clinical signs. ...
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Molecular responses to influenza A virus (IAV) infections vary between mammalian species. To identify conserved and species-specific molecular responses, we perform a comparative study of transcriptomic data derived from blood cells, primary epithelial cells, and lung tissues collected from IAV-infected humans, ferrets, and mice. The molecular responses in the human host have unique functions such as antigen processing that are not observed in mice or ferrets. Highly conserved gene coexpression modules across the three species are enriched for IAV infection-induced pathways including cell cycle and interferon (IFN) signaling. TDRD7 is predicted as an IFN-inducible host factor that is up-regulated upon IAV infection in the three species. TDRD7 is required for antiviral IFN response, potentially modulating IFN signaling via the JAK/STAT/IRF9 pathway. Identification of the common and species-specific molecular signatures, networks, and regulators of IAV infection provides insights into host-defense mechanisms and will facilitate the development of novel therapeutic interventions against IAV infection.
... Cannabinoid signaling can play a significant role in maintaining immune homeostasis and controlling the magnitude of immune response in various infections. In viral infections where the host inflammatory response is pathogenic (immunopathogenic), such as influenza, HCV, KSVH, RSV, and others, the cannabinoid receptor agonists have potential utility as anti-inflammatory and immunomodulatory agents for the treatment of many inflammatory diseases [84,124,125,137,142,143]. The cannabinoid receptors do not necessarily directly affect viral load; the relevance of cannabinoid receptors on viral infection appears to happen mainly through immune response manipulation by infiltrating the immune cells into the affected tissues. ...
The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established, however, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, and indirect mechanisms of inflammatory / autoimmune origin. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potential promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review we address the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a decrease in viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.
... However, CBD failed to alter the clinical disease development of COVID-19 when given at a daily dose of 300 mg for 14 days [267]. Additionally, caution should be taken into account due to the immunosuppressive activities of phytocannabinoids that can prevent proper anti-viral immune responses [268]. Notably, the use of Cannabis was increased in U.S. and Canada by 6-8% during the COVID-19 pandemic in comparison to the pre-pandemic period [269], with a special increase among people with mental health [270]. ...
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Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... Thus, it is likely that CBDA will have a similar safety profile to high-dose CBD, which is only found in some prescription products [18]. There is reason for caution with CBDA and then because CBDs immunomodulatory effects are associated with increased mortality and impaired immune defenses [18,21]. Other cannabinoids, such as THC, are also associated with increased risk of infection [19]. ...
Computational tools in drug discovery involve the use of algorithms in predicting properties of potential drugs as ligands as well as biological targets in structural forms. This dates back to more than 30 years ago and have been perfected with time and advancement of technology. They are reliable to varying extents depending on the nature of the study, complexity among other factors. Computational tools help medicinal chemists, computational chemists, and structural biologists to design and optimize potential drugs as early as possible and reduce or completely avoid attrition in the drug discovery pipeline. The search for drugs to cure or manage COVID-19 is made relatively easier and more efficient by the use of computational tools to help understand the ADMET properties of possible drugs under development. This chapter demonstrates how computational tools in cheminformatics and machine learning can be used in the fight against COVID-19 from a medicinal chemistry perspective using selected parameters.
The coronavirus disease 2019 (COVID-19) was identified as the cause of an outbreak of respiratory illness in Wuhan in 2019. Some of the antivirals presently being tried are known anti-HIV (combination of lopinavir and ritonavir) and the rejected anti-ebola virus (remdesivir) drugs. Others are chloroquine, hydroxychloroquine and azithromycin. Till date, there is no specific antiviral treatment that has proven effective in the management of the pandemic. The infected victims primarily rely on symptomatic treatments and supportive care. This COVID-19 outbreak has triggered researchers worldwide to embark on more high-quality researches, in addition to the preventive measures, to manage the public health emergency in both the short- and long-term. Membrane lipids like cholesterol, glycerophospholipids and sphingolipids play key role in modification of intracellular membrane structures for virus replication. This chapter discussed the roles of membrane lipids in coronavirus replication, and inhibition of lipids biosynthesis for possible management of coronavirus disease.
Drug repurposing involves the process of investigating already existing drugs with an aim to use them for different therapeutic purposes than the intended one. This approach is relatively faster, less costly, and reliable in terms of safety as the drug under study is already derisked and known for its other chemistry and pharmacokinetic properties. With these benefits in mind, it is a very reliable way to undertake drug development for emerging diseases such as COVID-19 which demand immediate interventions to slow or completely stop its havoc on mankind. One of the biggest challenges that drug repurposing has is the possibility of the occurrence of new mechanisms of action between the drug ligand and some proteins in the human physiology. Drug repurposing appears to have settled in the meantime in drug development, though more studies in the future will be warranted particularly in regards to resistance.
Coronavirus Drug Discovery SARS-CoV-2 (COVID-19) Prevention, Diagnosis, and Treatment
Various individuals, community organizations and institutions must be involved in planning and developing a cure for the COVID-19 flu pandemic. In addition to governmental organizations, those who need to be involved in the process are responsible for implementing pandemic plans. There should be a balance between centralized national control and regional and local communities through the effective implementation of the guidelines. There is a need to introduce social distancing and to study and isolate cases to contain disease spread. Due to the amendment and tightening of the law "SARS-CoV-2" in many countries, special attention should be paid to respect for citizens, especially national minorities. That is why it is necessary to protect freedom statements and providing access to critical information; make sure that quarantines, locks and travel bans comply with legal standards; persons.
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The endocannabinoid (EC) system mediates protection against intestinal inflammation. In this study, we investigated the effects of blocking EC degradation or cellular reuptake in experimental colitis in mice. Mice were treated with trinitrobenzene-sulfonic acid in presence and absence of the fatty acid amide hydrolase (FAAH) blocker URB597, the EC membrane transport inhibitor VDM11, and combinations of both. Inflammation was significantly reduced in the presence of URB597, VDM11, or both as evaluated by macroscopic damage score, myeloperoxidase levels, and colon length. These effects were abolished in CB1- and CB2-receptor-gene-deficient mice. Quantitative reverse transcription polymerase chain reaction after induction of experimental colitis by different pathways showed that expression of FAAH messenger RNA (mRNA) is significantly reduced in different models of inflammation early in the expression of colitis, and these return to control levels as the disease progresses. Genomic DNA from 202 patients with Crohn’s disease (CD) and 206 healthy controls was analyzed for the C385A polymorphism in the FAAH gene to address a possible role in humans. In our groups, the C385A polymorphism was equally distributed in patients with CD and healthy controls. In conclusion, drugs targeting EC degradation offer therapeutic potential in the treatment of inflammatory bowel diseases. Furthermore, reduction of FAAH mRNA expression is involved in the pathophysiological response to colitis.
Vesicular stomatitis virus (VSV), a natural epizootic among farm animals which is spread by sand-flies, has been used for experimental acute infections of mice since the 1930s when Sabin and Olitzky did pioneering investigations. This chapter will summarize the contributions of many laboratories to our understanding of host innate and adaptive immune responses, and viral evasion of innate responses. In addition, the potential power of this virus for vaccine platforms and oncolysis will be discussed. The virus has an evasive strategy which inhibits host cell gene expression. VSV readily elicits Type I Interferon (IFN) responses in the periphery, but fails to trigger this critical antiviral response in the CNS. VSV is a deceptively simple virus whose study has led to unexpected insights into the complexities of cell biology and host responses to infection. © 2009 by World Scientific Publishing Co. Pte. Ltd. All rights reserved.
Introduction Viruses enter the brain by many routes. Rabies virus enters via a bite from a rabid bat or animal, replicates locally, crosses the neuromuscular synapse, and travels retrograde to the central nervous system (CNS). Mosquitoes infected with West Nile virus (WNV) sting a bird or mammal; WNV replicates locally and then travels hematogenously, infecting the brain endothelium. Human immunodeficiency virus (HIV), whether the virus entered by injection or semen, enters lymph nodes, replicates, and then is carried to the brain by infected monocytes that traverse the microvascular endothelium and enter the perivascular space, ultimately transmitting HIV to microglia. Other viruses, such as reovirus, replicate in peripheral tissues, circulate as free infectious virions, and can infect the vascular endothelium of the CNS. Viruses can be inhaled and replicate in the olfactory neuroepithelium and spread caudally across the cribriforme plate along the olfactory nerve. Herpes simplex virus (HSV) can infect the eye (keratitis) or the oral or vaginal mucosa, enter the local nerve, and then be transmitted by retrograde passage to a ganglion and sometimes to the CNS, causing encephalitis. Once within the brain, viruses replicate in a variety of cell types and induce local innate immune responses. Every cell type (endothelial cells, ependymal cells, perivascular macrophages and pericytes, astrocytes, microglia, oligodendrocyes, Schwann cells, and neurons) in the CNS can be infected by different viruses. Viral infections of the CNS challenge the host with a different set of problems than do peripheral viral infections. © Cambridge University Press 2008 and Cambridge University Press, 2009.
Both herpes simplex virus type I (HSV-I) and herpes simplex virus type 2 (HSV-2) failed, in an identical fashion to replicate and produce extensive c.p.e. in human cell monolayer cultures which were exposed (8 h before infection, at infection, or 8 h p.i.) to various concentrations of Δ-9-tetrahydrocannabinol. Similar results were obtained with a plaque assay utilizing confluent monkey cells. Possible mechanisms for this antiviral activity are discussed.
ASTROCYTES are an important cell population in the CNS, involved in cytokine homeostasis and participating in a variety of important physiological and pathological processes. In the present study we showed that primary cultures of neonatal mouse cortical astrocytes stimulated with lipopolysaccharide (Balb/c mice strain, LPS: 1 mu g/ml, 18 h) or Theiler's virus, TMEV (SJL/J mice strain, TMEV: 10(5) PFU/well, 24h) released an increased amount of nitrites (NO2-) and tumour necrosis factor-alpha (TNF-alpha) into the culture medium. Exogenous cannabinoids are known to modulate the function of immune cells. Anandamide, an endogenous ligand for the cannabinoid receptor, blocked the release of NO2- and TNF-alpha induced by LPS in a dose-dependent manner. In TMEV-stimulated astrocytes anandamide also suppressed, in a dose-related manner, the stimulatory effects of TMEV on both NO2- and TNF-alpha. It is suggested that anandamide exerts an immunoregulatory role in the CNS. These results could have important implications in the modulation of immunological and inflammatory processes by cannabinoid agents.
Adhesion molecules are critical players in the regulation of transmigration of blood leukocytes across the blood–brain barrier in multiple sclerosis (MS). Cannabinoids (CBs) are potential therapeutic agents in the treatment of MS, but the mechanisms involved are only partially known. Using a viral model of MS we observed that the cannabinoid agonist WIN55,212-2 administered at the time of virus infection suppresses intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in brain endothelium, together with a reduction in perivascular CD4+ T lymphocytes infiltrates and microglial responses. WIN55,212-2 also interferes with later progression of the disease by reducing symptomatology and neuroinflammation. In vitro data from brain endothelial cell cultures, provide the first evidence of a role of peroxisome proliferator-activated receptors gamma (PPARγ) in WIN55,212-2-induced downregulation of VCAM-1. This study highlights that inhibition of brain adhesion molecules by WIN55,212-2 might underline its therapeutic effects in MS models by targeting PPAR-γ receptors.
Cannabinoids have recently been approved as a treatment for pain in multiple sclerosis (MS). Increasing evidence from animal studies suggests that this class of compounds could also prove efficient to fight neurodegeneration, demyelination, inflammation and autoimmune processes occurring in this pathology. However, the use of cannabinoids is limited by their psychoactive effects. In this context, potentiation of the endogenous cannabinoid signalling could represent a substitute to the use of exogenously administrated cannabinoid ligands. Here, we studied the expression of different elements of the endocannabinoid system in a chronic model of MS in mice. We first studied the expression of the two cannabinoid receptors, CB(1) and CB(2), as well as the putative intracellular cannabinoid receptor peroxisome proliferator-activated receptor-alpha. We observed an upregulation of CB(2), correlated to the production of proinflammatory cytokines, at 60 days after the onset of the MS model. At this time, the levels of the endocannabinoid, 2-arachidonoylglycerol, and of the anti-inflammatory anandamide congener, palmithoylethanolamide, were enhanced, without changes in the levels of anandamide. These changes were not due to differences in the expression of the degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, or of biosynthetic enzymes, diacylglycerol lipase-alpha and N-acylphosphatidylethanolamine phospholipase-D at this time (60 days). Finally, the exogenous administration of palmitoylethanolamide resulted in a reduction of motor disability in the animals subjected to this model of MS, accompanied by an anti-inflammatory effect. This study overall highlights the potential therapeutic effects of endocannabinoids in MS.
Many virus infections elicit vigorous host immune responses, both innate and acquired. The immune responses are fre- quently successful in controlling and then clearing the virus, using both cellular effectors such as natural killer (NK) cells and cytolytic T lymphocytes and soluble factors such as inter- ferons (IFNs). However, some immune responses lead to pathologic changes or are unable to prevent the pathogen's growth. This review will not be devoted to the different strat- egies viruses have taken to promote their transmission or sur- vival but rather to one aspect of the innate immune response to infection: the role of nitric oxide (NO) in the antiviral reper- toire. Recently, data from many laboratories, using both RNA and DNA viruses in experimental systems, have implicated a role for NO in the immune response. The data do not indicate a magic bullet for all systems but suggest that NO may inhibit an early stage in viral replication and thus prevent viral spread, promoting viral clearance and recovery of the host. The earliest host responses to viral infections are nonspecific and involve the induction of cytokines, among them, IFNs and tumor necrosis factor alpha (TNF-a). Gamma IFN (IFN-g) and TNF-a have both been shown to be active in many cell types and induce cascades of downstream mediators (reviewed in references 25, 34, and 41). Others have found that NO synthase type 2 (NOS-2, iNOS) is an IFN-g-inducible protein in macrophages, requiring IRF-1 as a transcription factor (12, 17). We have observed that the isoform expressed in neurons, NOS-1, is IFN-g, TNF-a, and interleukin-12 (IL-12) inducible (20). Thus, NOS falls into the category of IFN-inducible pro- teins, activated during innate immune responses. NO is produced by the enzymatic modification of L-arginine to L-citrulline and requires many cofactors, including tetrahy- drobiopterine, calmodulin, NADPH, and O2. NO rapidly re- acts with proteins or with H2O2 to form ONOO 2 , peroxyni-