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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
pharmaceuticals
ISSN 1424-8247
www.mdpi.com/journal/pharmaceuticals
Review
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: carol.reiss@nyu.edu; 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
2+
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
1
or the CB
2
receptor, which are found on distinct cell
types. The CB
1
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
1
receptor by its endogenous
or exogenous agonists may inhibit the release of Ca
2+
from intracellular or extracellular stores. Since
many important intracellular proteins are Ca
2+
-dependent for activation, signal transduction through
the CB
1
receptor may impair these secondary pathways and have a profound influence on the ability of
viruses to replicate in neurons.
OPEN ACCESS
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In contrast, the response of cells expressing the CB
2
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
2+
-dependent
enzymes. Table 1 indicates some of the well characterized pathways involved and their potential
impact on viral infections.
The common recurring impact of Ca
2+
-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
2+
-dependent enzymes which may be inhibited by Cannabinoids and
speculated role in host responses relevant for viral infections.
Enzyme
primary/secondary
Pathways
Ref.
Role(s) in viral
infection-host
responses
cPhospholipase A
2
Arachidonic acid metabolites (prostaglandins,
leukotrienes, lipoxins, resolvins) and
inflammation
[1,2] Inflammation and its
resolution
Phospholipase C
- Receptor-mediated tyrosine
kinase
Production of Inositol 1,4,5-triphosphate from
phosophotidylinositol
[3] Signal transduction
Phospholipase D
1
Exocytosis in neuroendocrine cells [4] Neurotransmission
Calcineurin Activation of NFAT—gene expression [5,6] Signal transduction
Ca
2+
-Calmodulin
- Nitric oxide synthase-1
- Nitric oxide synthase-3
Conversion of argenine to NO in neurons and
endothelial cells; production of ONOO-, -SNO,
-R-NO
2
Inhibition of viral infection
[7–12]
Anti-viral; NO
2
-
decoration of viral
proteins; capillary
dilation; inflammation
Ca
2+
-Calmodulin dependent
protein kinases
- CREB
- CaMKK activation of
AMPK
Wnt-2-dependent dendrite growth &
cardiomyogenesis
Energy, epithelial cell polarity
T cell activation
[13–17] Adaptive immune
responses;
inflammation
Calpains [Ca
2+
-dependent
proteases]
Neutral proteases [many tissues]
Cell membrane fusion, synaptic remodeling,
activating PKC, remodeling cytoskeleton,
transcription factors
[18–20] Cytoskeletal plasticity,
cell migration,
inflammation
Matrix metalloproteinases Extracellular matrix remodeling, inflammation [21] Inflammation
Calpastatin Cell fusion in fertilization [22] Formation of
heterokaryons
/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.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
HSV-2,
L. monocyto-
genes
In vivo Δ9-THC decreased
resistance to
LD
50
systemic infection [29]
HSV-2 In vivo Δ9-THC increased
shedding
increased
severity of
lesions &
mortality
delayed onset of
DTH response
vaginal model
B6C3H F
1
mouse
[30]
HSV-2 In vivo Δ9-THC decreased Type I
IFN response
i.v. infection [31]
HSV-2 In vivo Δ9-THC decreased
resistance to
infection;
increased
severity of
lesions
vaginal guinea pig
model
[32]
HSV-1,-2 In
vitro
Δ9-THC failed to
replicate
antiviral effect in
human & monkey
cells
[33]
HSV-2 In
vitro
Δ9-THC 100-fold
increase in
released
virus
Vero cells,
increased CPE
[34]
HSV-2 both Δ9-THC decreased T cell
proliferation
B6C3H F
1
mice
immunized then T
cells cultured
[35]
HSV In
vitro
Δ9-THC decreased
infectivity
in TC
virus incubated
with THC
[36]
HSV-1 both Δ9-THC decreased CD8
CTL activity
C3H mice
immunized, L929
targets
[37]
EBV,
KSHV,
HVS,
HSV-1,
MHV-68
In vivo Δ9-THC Immediate
early ORF
promoter
activity
inhibited
reactivation
from latency
inhibited
latently infected B
cells in tissue
culture
[38]
KSHV In vivo Δ9-THC increased
viral load
increased
efficiency of
infection,
activation of
lytic switch
increased
transformation of
endothelial cells
primary human
dermal
microvascular cells
[39]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
Cowpox In vivo Marijuana
cigarettes
generalized
infection
weak Ab
production, no
neutralizing Abs
Case report [40]
TMEV In
vitro
Anandamide decreased release
of NO2- and
TNF-α
NO is antiviral for
TMEV
[41;42]
TMEV In
vitro
Anandamide increased IL-6
production
astrocyte culture
B6 and SJL mice
[43]
TMEV In vivo WIN-55,212 ameliorates
progression of
autoimmune
disease TMEV-
IDD
decreased DTH,
decreased IL-1,
IL-6, IFN-
γ , TNF-α,
TMEV-IDD a
mouse model of
MS
[44]
TMEV In vivo OMDM1,
OMDM2
ameliorated
motor
symptoms
decreased MHC
II, inhibited
NOS-2, reduced
proinflammatory
cytokines
TMEV-IDD
proposed MS
therapy with
cannabinoids
[45]
TMEV In
vitro
JWH-133
SR144558
role of CB
2
receptors in
anti-
inflammatory
actions
reduced IL-
12p40, reduced
ERK1/2
signaling
[46]
TMEV In
vitro
WIN-55,212 CB
2
-dependent
COX-2
induction
increased vs.
TMEV-alone
role of PI3 kinase
pathway in CB
2
but MAPK for
TMEV signaling
proposed role on
blood-flow and
immune activity
[47]
TMEV In vivo Palmitoyl-
ethanol-
amine
reduction in
motor disability
in TMEV-IDD
anti-
inflammatory
effect
TMEV-IDD
[48]
TMEV both WIN-55,212 inhibited ICAM
& VCAM on
endothelium;
role for PPAR-γ
receptors in
mechanism
reduced
inflammation
TMEV-IDD
[49]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
Influenza In vivo Δ9-THC HA mRNA
increased
inflammation,
metaplasia of
mucous cell
decreased CD4,
CD8, and
macrophage
recruitment
[50]
Influenza In vivo Δ9-THC HA mRNA
decreased in
CB
1
/CB
2
KO
mice
THC-mediated
airway
pathology +/-
CB
1
/CB
2
KO mice had
increased CD4
and IFN-γ
recruitment
CB
1
/CB
2
KO mice [51]
VSV In vitro WIN-55,212 increased
viral titers
CB
1
-dependent;
decreased NOS-
1 activity
antagonized IFN-
γ-mediated
antiviral pathway
suggested disease
progression likely
in neurons/viral
encephalitis
[52]
BDV In vivo WIN-55,212 protected BrdU-
positive neural
progenitor cells
in striatum
suppressed
microglial
activation
suggested treatment
of encephalitis with
microglial
inflammation and
neuro-degeneration
[53]
HCV In vivo Marijuana
cigarettes
progression of
liver fibrosis
epidemiological
study
[54]
HCV In vivo Oral
cannabinoids
improved
weight
no viral markers
or immune
markers studied
7 week clinical trial
for anorexia and
nausea
[55]
HCV In vivo Marijuana
cigarettes
progression of
liver fibrosis;
increased
disease severity
clinical
pathological survey
of 204 HCV
patients
[56]
HIV-1 In vitro Δ9-THC, CP-
55,940, WIN-
55,212
increased syn-
cytia formation
MT-2 cells
(CB
1
& CB
2
+
)
speculate
cannabinoids
enhance HIV-1
infection
[57]
HIV-1 In vitro anandamide increased
adherence for
monocytes
uncoupled NO
release, inhibited
NO
human saphenous
vein or internal
thoracic artery;
speculate higher
titers in vivo
[58]
HIV-1 Tat In vitro WIN-55,212 reduced tat-
induced
cytotoxicity
inhibited NOS-2
activity
C6 rat glioma cell
line
[59]
HIV-1 In vivo Marijuana
cigarettes
increased
appetite
insufficient
numbers of
individuals
3 week trial [60]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
HIV-1 In vivo Marijuana
cigarettes
mRNA
unchanged
CD4+ and CD8+
cells unchanged
3 week trial,
placebo-controlled
[61]
HIV-1 WIN-55,212 inhibited
expression
CD4 and microglial
cultures
[62]
HIV-1 In vivo THC increased
viral
replica-tion
50-fold
decreased CD4
IFN-γ-producing
cells, increased
co-receptor
expression
scid-Hu mouse
model
[63]
HIV-1
Gp120
In
vitro
2-AG,
CP55940
inhibited Ca
+2
-
flux-induced
substance P,
decreased
permeability
model of BBB, co-
culture of Human
brain microvascular
endothelial cells
and astrocytes
[64]
HIV-1 In vivo WIN-55,212 dose-related
hypothermia in
mouse pre-optic
anterior
hypothalamus
infusion
WIN-55,212 is
antagonist for
SDF-1a/
CXCL12/
CXCR4 [HIV-1
coReceptor]
pathway
mouse model for
HIV-thermoreg-
ulation by direct
injection of WIN-
55,212 to brain
POAH center
[65]
HIV-1 Tat In
vitro
CP55940,
Δ9-THC
CB
2
-dependent
inhibition of
U937 migration
to Tat
possible anti-
inflammatory
mechanism
U937 cells in
culture
[66]
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
2+
-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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Acknowledgements
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.
References
1. Bannenberg, G.L.; Chiang, N.; Ariel, A.; Arita, M.; Tjonahen, E.; Gotlinger, K.H.; Hong, S.;
Serhan, C.N. Molecular circuits of resolution: Formation and actions of resolvins and protectins. J.
Immunol. 2005, 174, 4345–4355.
2. Machado, F.S.; Johndrow, J.E.; Esper, L.; Dias, A.; Bafica, A.; Serhan, C.N.; Aliberti, J. Anti-
inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat.
Med. 2006, 12, 330–334.
3. Morita, M.; Yoshiki, F.; Nakane, A.; Okubo, Y.; Kudo, Y. Receptor- and calcium-dependent
induced inositol 1,4,5-trisphosphate increases in PC12h cells as shown by fluorescence resonance
energy transfer imaging. FEBS J. 2007, 274, 5147–5157.
4. Vitale, N. Synthesis of fusogenic lipids through activation of phospholipase D1 by GTPases and
the kinase RSK2 is required for calcium-regulated exocytosis in neuroendocrine cells. Biochem.
Soc. Trans. 2010, 38, 167–171.
5. Oh-hora, M.; Rao, A. The calcium/NFAT pathway: Role in development and function of
regulatory T cells. Microbes Infect. 2009, 11, 612–619.
6. Rao, A. Signaling to gene expression: Calcium, calcineurin and NFAT. Nat. Immunol. 2009,
10, 3–5.
7. Knowles, R.G.; Moncada, S. Nitric oxide synthases in mammals. Biochem. J. 1994,
298, 249–258.
8. Lopez-Jaramillo, P.; Teran, E.; Moncada, S. Calcium supplementation prevents pregnancy-
induced hypertension by increasing the production of vascular nitric oxide. Med. Hypotheses 1995,
45, 68–72.
9. Edelstein, C.L.; Yaqoob, M.M.; Schrier, R.W. The role of the calcium-dependent enzymes nitric
oxide synthase and calpain in hypoxia-induced proximal tubule injury. Ren Fail. 1996, 18,
501–511.
10. Reiss, C.S.; Komatsu, T. Does nitric oxide play a critical role in viral infections? J. Virol. 1998,
72, 4547–4551.
11. Akaike, T.; Maeda, H. Nitric oxide and virus infection. Immunology 2000, 101, 300–308.
12. Akuta, T.; Zaki, M.H.; Yoshitake, J.; Okamoto, T.; Akaike, T. Nitrative stress through formation
of 8-nitroguanosine: Insights into microbial pathogenesis. Nitric. Oxide. 2006, 14, 101–108.
13. Alvania, R.S.; Chen, X.; Ginty, D.D. Calcium signals control Wnt-dependent dendrite growth.
Neuron 2006, 50, 813–815.
Pharmaceuticals 2010, 3
1882
14. Wayman, G.A.; Impey, S.; Marks, D.; Saneyoshi, T.; Grant, W.F.; Derkach, V.; Soderling, T.R.
Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced
CREB-dependent transcription of Wnt-2. Neuron 2006, 50, 897–909.
15. Flaherty, M.P.; Dawn, B. Noncanonical Wnt11 signaling and cardiomyogenic differentiation.
Trends Cardiovasc. Med. 2008, 18, 260–268.
16. Caplan, M.J.; Seo-Mayer, P.; Zhang, L. Epithelial junctions and polarity: Complexes and kinases.
Curr. Opin. Nephrol. Hypertens. 2008, 17, 506–512.
17. Liu, J.O. Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved
in T-cell activation. Immunol. Rev. 2009, 228, 184–198.
18. Pontremoli, S.; Melloni, E. Extralysosomal protein degradation. Annu. Rev Biochem. 1986, 55,
455–481.
19. Mellgren, R.L. Calcium-dependent proteases: An enzyme system active at cellular membranes?
FASEB J. 1987, 1, 110–115.
20. Dargelos, E.; Poussard, S.; Brule, C.; Daury, L.; Cottin, P. Calcium-dependent proteolytic system
and muscle dysfunctions: a possible role of calpains in sarcopenia. Biochimie 2008, 90, 359–368.
21. Consolo, M.; Amoroso, A.; Spandidos, D.A.; Mazzarino, M.C. Matrix metalloproteinases and
their inhibitors as markers of inflammation and fibrosis in chronic liver disease (Review). Int. J.
Mol. Med. 2009, 24, 143–152.
22. Rojas, F.J.; Brush, M.; Moretti-Rojas, I. Calpain-calpastatin: A novel, complete calcium-
dependent protease system in human spermatozoa. Mol. Hum. Reprod. 1999, 5, 520–526.
23. Elli, L.; Bergamini, C.M.; Bardella, M.T.; Schuppan, D. Transglutaminases in inflammation and
fibrosis of the gastrointestinal tract and the liver. Dig. Liver Dis. 2009, 41, 541–550.
24. Reiss, C.S. Innate immunity in viral encephalitis. In Neurotropic Virus Infections. Cambridge
University Press: Cambridge, UK, 2008, pp. 265–291.
25. Reiss, C.S. VSV infection elicits distinct host responses in the periphery and the brain. In RNA
Viruses: Host Gene Responses to Infection; Yang, D., ed. World Scientific Publishing:
Hackensack, NJ, USA, 2009; pp. 229–246.
26. Klein, T.W.; Friedman, H.; Specter, S. Marijuana, immunity and infection. J. Neuroimmunol.
1998, 83, 102–115.
27. Bani, D.; Mannaioni, G.; Passani, M.B.; Masini, E. Role of cannaboboids in the modulation f
inflammatory processes.
Pharmaceuticals 2010, submitted.
28. Klein, T.W.; Cabral, G.A. Cannabinoid-induced immune suppression and modulation of antigen-
presenting cells. J. Neuroimmune. Pharmacol. 2006, 1, 50–64.
29. Morahan, P.S.; Klykken, P.C.; Smith, S.H.; Harris, L.S.; Munson, A.E. Effects of cannabinoids on
host resistance to Listeria monocytogenes and herpes simplex virus. Infect. Immun. 1979, 23,
670–674.
30. Mishkin, E.M.; Cabral, G.A. Delta-9-Tetrahydrocannabinol decreases host resistance to herpes
simplex virus type 2 vaginal infection in the B6C3F1 mouse. J. Gen. Virol. 1985, 66, 2539–2549.
31. Cabral, G.A.; Lockmuller, J.C.; Mishkin, E.M. Delta 9-tetrahydrocannabinol decreases alpha/beta
interferon response to herpes simplex virus type 2 in the B6C3F1 mouse. Proc. Soc. Exp. Biol.
Med. 1986, 181, 305–311.
Pharmaceuticals 2010, 3
1883
32. Cabral, G.A.; Mishkin, E.M.; Marciano-Cabral, F.; Coleman, P.; Harris, L.; Munson, A.E. Effect
of delta 9-tetrahydrocannabinol on herpes simplex virus type 2 vaginal infection in the guinea pig.
Proc. Soc. Exp. Biol. Med. 1986, 182, 181–186.
33. Blevins, R.D.; Dumic, M.P. The effect of delta-9-tetrahydrocannabinol on herpes simplex virus
replication. J. Gen. Virol. 1980, 49, 427–431.
34. Cabral, G.A.; McNerney, P.J.; Mishkin, E.M. Delta-9-tetrahydrocannabinol enhances release of
herpes simplex virus type 2. J. Gen. Virol. 1986, 67, 2017–2022.
35. Cabral, G.A.; McNerney, P.J.; Mishkin, E.M. Delta-9-tetrahydrocannabinol inhibits the
splenocyte proliferative response to herpes simplex virus type 2. Immunopharmacol.
Immunotoxicol. 1987, 9, 361–370.
36. Lancz, G.; Specter, S.; Brown, H.K. Suppressive effect of delta-9-tetrahydrocannabinol on herpes
simplex virus infectivity in vitro. Proc. Soc. Exp. Biol. Med. 1991, 196, 401–404.
37. Fischer-Stenger, K.; Updegrove, A.W.; Cabral, G.A. Delta 9-tetrahydrocannabinol decreases
cytotoxic T lymphocyte activity to herpes simplex virus type 1-infected cells. Proc. Soc. Exp. Biol.
Med. 1992, 200, 422–430.
38. Medveczky, M.M.; Sherwood, T.A.; Klein, T.W.; Friedman, H.; Medveczky, P.G. Delta-9
tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro.
BMC. Med. 2004, 2, 34.
39. Zhang, X.; Wang, J.F.; Kunos, G.; Groopman, J.E. Cannabinoid modulation of Kaposi's sarcoma-
associated herpesvirus infection and transformation. Cancer Res. 2007, 67, 7230–7237.
40. Huemer, H.P.; Himmelreich, A.; Honlinger, B.; Pavlic, M.; Eisendle, K.; Hopfl, R.; Rabl, W.;
Czerny, C.P. "Recreational" drug abuse associated with failure to mount a proper antibody
response after a generalised orthopoxvirus infection. Infection 2007, 35, 469–473.
41. Molina-Holgado, F.; Lledo, A.; Guaza, C. Anandamide suppresses nitric oxide and TNF-alpha
responses to Theiler's virus or endotoxin in astrocytes. Neuroreport 1997, 8, 1929–1933.
42. Oleszak, E.L.; Katsetos, C.D.; Kuzmak, J.; Varadhachary, A. Inducible nitric oxide synthase in
Theiler's murine encephalomyelitis virus infection. J. Virol. 1997, 71, 3228–3235.
43. Molina-Holgado, F.; Molina-Holgado, E.; Guaza, C. The endogenous cannabinoid anandamide
potentiates interleukin-6 production by astrocytes infected with Theiler's murine
encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett. 1998,
433, 139–142.
44. Croxford, J.L.; Miller, S.D. Immunoregulation of a viral model of multiple sclerosis using the
synthetic cannabinoid R(+)WIN55,212. J. Clin. Invest. 2003, 111, 1231–1240.
45. Mestre, L.; Correa, F.; Arevalo-Martin, A.; Molina-Holgado, E.; Valenti, M.; Ortar, G.; Di Marzo,
V.; Guaza, C. Pharmacological modulation of the endocannabinoid system in a viral model of
multiple sclerosis. J. Neurochem. 2005, 92, 1327–1339.
46. Correa, F.; Mestre, L.; Docagne, F.; Guaza, C. Activation of cannabinoid CB2 receptor negatively
regulates IL-12p40 production in murine macrophages: Role of IL-10 and ERK1/2 kinase
signaling. Br. J. Pharmacol. 2005, 145, 441–448.
47. Mestre, L.; Correa, F.; Docagne, F.; Clemente, D.; Guaza, C. The synthetic cannabinoid WIN
55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells
following Theiler's virus infection. Biochem. Pharmacol. 2006, 72, 869–880.
Pharmaceuticals 2010, 3
1884
48. Loria, F.; Petrosino, S.; Mestre, L.; Spagnolo, A.; Correa, F.; Hernangomez, M.; Guaza, C.; Di
Marzo, V.; Docagne, F. Study of the regulation of the endocannabinoid system in a virus model of
multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide. Eur. J. Neurosci 2008, 28,
633–641.
49. Mestre, L.; Docagne, F.; Correa, F.; Loria, F.; Hernangomez, M.; Borrell, J.; Guaza, C. A
cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by
downregulating adhesion molecules. Mol. Cell. Neurosci. 2009, 40, 258–266.
50. Buchweitz, J.P.; Karmaus, P.W.; Harkema, J.R.; Williams, K.J.; Kaminski, N.E. Modulation of
airway responses to influenza A/PR/8/34 by Delta9-tetrahydrocannabinol in C57BL/6 mice. J.
Pharmacol. Exp. Ther. 2007, 323, 675–683.
51. Buchweitz, J.P.; Karmaus, P.W.; Williams, K.J.; Harkema, J.R.; Kaminski, N.E. Targeted deletion
of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza
A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol. J. Leukoc. Biol. 2008, 83,
785–796.
52. Herrera, R.A.; Oved, J.H.; Reiss, C.S. Disruption of the IFN-g-mediated antiviral activity in
neurons: The role of Cannabinoids. Viral Immunol. 2008, 21, 141–152.
53. Solbrig, M.V.; Hermanowicz, N. Cannabinoid rescue of striatal progenitor cells in chronic Borna
disease viral encephalitis in rats. J. Neurovirol. 2008, 14, 252–260.
54. Hezode, C.; Roudot-Thoraval, F.; Nguyen, S.; Grenard, P.; Julien, B.; Zafrani, E.S.; Pawlotsky,
J.M.; Dhumeaux, D.; Lotersztajn, S.; Mallat, A. Daily cannabis smoking as a risk factor for
progression of fibrosis in chronic hepatitis C. Hepatology 2005, 42, 63–71.
55. Costiniuk, C.T.; Mills, E.; Cooper, C.L. Evaluation of oral cannabinoid-containing medications
for the management of interferon and ribavirin-induced anorexia, nausea and weight loss in
patients treated for chronic hepatitis C virus. Can. J. Gastroenterol. 2008, 22, 376–380.
56. Ishida, J.H.; Peters, M.G.; Jin, C.; Louie, K.; Tan, V.; Bacchetti, P.; Terrault, N.A. Influence of
cannabis use on severity of hepatitis C disease. Clin Gastroenterol. Hepatol. 2008, 6, 69–75.
57. Noe, S.N.; Nyland, S.B.; Ugen, K.; Friedman, H.; Klein, T.W. Cannabinoid receptor agonists
enhance syncytia formation in MT-2 cells infected with cell free HIV-1MN. Adv. Exp. Med. Biol.
1998, 437, 223–229.
58. Stefano, G.B.; Salzet, M.; Bilfinger, T.V. Long-term exposure of human blood vessels to HIV
gp120, morphine, and anandamide increases endothelial adhesion of monocytes: Uncoupling of
nitric oxide release. J. Cardiovasc. Pharmacol. 1998, 31, 862–868.
59. Esposito, G.; Ligresti, A.; Izzo, A.A.; Bisogno, T.; Ruvo, M.; Di Rosa, M.; Di Marzo, V.; Iuvone,
T. The endocannabinoid system protects rat glioma cells against HIV-1 Tat protein-induced
cytotoxicity: Mechanism and regulation. J. Biol. Chem. 2002, 277, 50348–50354.
60. Bredt, B.M.; Higuera-Alhino, D.; Shade, S.B.; Hebert, S.J.; McCune, J.M.; Abrams, D.I.
Short-term effects of cannabinoids on immune phenotype and function in HIV-1-infected patients.
J. Clin. Pharmacol. 2002, 42, 82S–89S.
61. Abrams, D.I.; Hilton, J.F.; Leiser, R.J.; Shade, S.B.; Elbeik, T.A.; Aweeka, F.T.; Benowitz, N.L.;
Bredt, B.M.; Kosel, B.; Aberg, J.A.; et al. Short-term effects of cannabinoids in patients with
HIV-1 infection: A randomized, placebo-controlled clinical trial. Ann. Intern. Med. 2003, 139,
258–266.
Pharmaceuticals 2010, 3
1885
62. Peterson, P.K.; Gekker, G.; Hu, S.; Cabral, G.; Lokensgard, J.R. Cannabinoids and morphine
differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J.
Neuroimmunol. 2004, 147, 123–126.
63. Roth, M.D.; Tashkin, D.P.; Whittaker, K.M.; Choi, R.; Baldwin, G.C. Tetrahydrocannabinol
suppresses immune function and enhances HIV replication in the huPBL-SCID mouse. Life Sci.
2005, 77, 1711–1722.
64. Lu, T.S.; Avraham, H.K.; Seng, S.; Tachado, S.D.; Koziel, H.; Makriyannis, A.; Avraham, S.
Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J.
Immunol. 2008, 181, 6406–6416.
65. Benamar, K.; Yondorf, M.; Meissler, J.J.; Geller, E.B.; Tallarida, R.J.; Eisenstein, T.K.; Adler,
M.W. A novel role of cannabinoids: Implication in the fever induced by bacterial
lipopolysaccharide. J. Pharmacol. Exp. Ther. 2007, 320, 1127–1133.
66. Raborn, E.S.; Cabral, G.A. Cannabinoid inhibition of macrophage migration to the TAT protein
of HIV-1 is linked to the CB
2
cannabinoid receptor. J. Pharmacol. Exp. Ther. 2010,
[doi: 10.1124/jpet.109.163055].
67. Jakob, J.; Roos, R.P. Molecular determinants of Theiler's murine encephalomyelitis-induced
disease. J. Neurovirol. 1996, 2, 70–77.
68. Olson, J.K.; Miller, S.D. The innate immune response affects the development of the autoimmune
response in Theiler's virus-induced demyelinating disease. J. Immunol. 2009, 182, 5712–5722.
69. Villarreal, D.; Young, C.R.; Storts, R.; Ting, J.W.; Welsh, C.J. A comparison of the neurotropism
of Theiler's virus and poliovirus in CBA mice. Microb. Pathog. 2006, 41, 149–156.
70. Dietzschold, B.; Morimoto, K. Signaling pathways in virus-induced CNS inflammation. J.
Neurovirol. 1997, 3 (Suppl. 1), S58–S59.
71. Gosztonyi, G.; Ludwig, H. Borna disease--neuropathology and pathogenesis. Curr. Top.
Microbiol. Immunol. 1995, 190, 39–73.
72. Hooper, D.C.; Kean, R.B.; Scott, G.S.; Spitsin, S.V.; Mikheeva, T.; Morimoto, K.; Bette, M.;
Rohrenbeck, A.M.; Dietzschold, B.; Weihe, E. The central nervous system inflammatory response
to neurotropic virus infection is peroxynitrite dependent. J. Immunol. 2001, 167, 3470–3477.
73. Rohrenbeck, A.M.; Bette, M.; Hooper, D.C.; Nyberg, F.; Eiden, L.E.; Dietzschold, B.; Weihe, E.
Upregulation of COX-2 and CGRP expression in resident cells of the Borna disease virus-infected
brain is dependent upon inflammation. Neurobiol. Dis. 1999, 6, 15–34.
74. Cabral, G.A.; Dove Pettit, D.A. Drugs and immunity: Cannabinoids and their role in decreased
resistance to infectious disease. J. Neuroimmunol. 1998, 83, 116–123.
75. Munckhof, W.J.; Konstantinos, A.; Wamsley, M.; Mortlock, M.; Gilpin, C. A cluster of
tuberculosis associated with use of a marijuana water pipe. Int. J Tuberc. Lung Dis. 2003,
7, 860–865.
76. Han, B.; Gfroerer, J.C.; Colliver, J.D. Associations between duration of illicit drug use and health
conditions: Results from the 2005–2007 national surveys on drug use and health. Ann. Epidemiol.
2010, 20, 289–297.
77. Holtz, T.H.; Lancaster, J.; Laserson, K.F.; Wells, C.D.; Thorpe, L.; Weyer, K. Risk factors
associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999–2001.
Int. J. Tuberc. Lung Dis. 2006, 10, 649–655.
Pharmaceuticals 2010, 3
1886
78. Cabral, G.A.; Marciano-Cabral, F. Cannabinoid-mediated exacerbation of brain infection by
opportunistic amebae. J. Neuroimmunol. 2004, 147, 127–130.
79. Marciano-Cabral, F.; Raborn, E.S.; Martin, B.R.; Cabral, G.A. Delta-9-tetrahydrocannabinol, the
major psychoactive component in marijuana, inhibits macrophage chemotaxis to Acanthamoeba. J.
Eukaryot. Microbiol. 2006, 53 (Suppl. 1), S15–S17.
80. Benamar, K.; Yondorf, M.; Geller, E.B.; Eisenstein, T.K.; Adler, M.W. Physiological evidence
for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain.
Br. J. Pharmacol. 2009, 157, 1225–1231.
81. Smith, S.R.; Terminelli, C.; Denhardt, G. Modulation of cytokine responses in Corynebacterium
parvum-primed endotoxemic mice by centrally administered cannabinoid ligands. Eur. J.
Pharmacol. 2001, 425, 73–83.
82. Bass, R.; Engelhard, D.; Trembovler, V.; Shohami, E. A novel nonpsychotropic cannabinoid, HU-
211, in the treatment of experimental pneumococcal meningitis. J. Infect. Dis. 1996,
173, 735–738.
83. Storr, M.A.; Yuce, B.; Andrews, C.N.; Sharkey, K.A. The role of the endocannabinoid system in
the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol. Motil. 2008,
20, 857–868.
84. Storr, M.A.; Keenan, C.M.; Emmerdinger, D.; Zhang, H.; Yuce, B.; Sibaev, A.; Massa, F.;
Buckley, N.E.; Lutz, B.; Goke, B.; et al. Targeting endocannabinoid degradation protects against
experimental colitis in mice: Involvement of CB1 and CB2 receptors. J. Mol. Med. 2008,
86, 925–936.
85. Elikkottil, J.; Gupta, P.; Gupta, K. The analgesic potential of cannabinoids. J. Opioid. Manag.
2009, 5, 341–357.
86. Aggarwal, S.K.; Carter, G.T.; Sullivan, M.D.; ZumBrunnen, C.; Morrill, R.; Mayer, J.D.
Medicinal use of cannabis in the United States: Historical perspectives, current trends, and future
directions. J. Opioid. Manag. 2009, 5, 153–168.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).
... As a result, similar to other coronaviruses, excessive levels of cytokines produced in host cells cause cytokine storms [25,33]. The activation of innate and acquired immune systems should be activated for early detection of the virus, control of replication, and faster disease recovery [121]. The inflammatory cytokines trigger innate immunity. ...
... THC reduces inflammation through various pathways involving CB1 and CB2 receptors, T cell modulation, epigenetic changes, induction of anti-inflammatory cells (MDSCs), and regulation of SOCS1 and miRNA to dampen cytokine storms. Animal studies confirm THC's ability to inhibit cytokine storms by activating CB2 receptors and blocking migration of immune cells into the lungs [36,121]. The researchers showed that THC could reduce the production of IgM antibodies in the spleen of mice and humans by disrupting the formation of plasma cells and activation of primary B cells [97]. ...
... CB1 receptors, discovered in 1988, are found throughout the central nervous system (CNS) and periphery, including the frontal cortex, limbic system, hypothalamus, sensory and motor areas, medulla, pons, and some astrocytes and skeletal muscle cells. CB1 agonists can suppress inflammation, and CB1 expression in the lung and liver may impact viral infection [121,145,149]. For instance, in RSV infection of mice, CB1 agonist administration reduces pulmonary complications. ...
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The COVID-19 pandemic is a global health crisis affecting millions of people worldwide. Along with vaccine development, there is also a priority to discover new drugs and treatments. One approach involves modulating the immune system to manage inflammation and cytokine storms. Patients with a high severity of complications exhibit a high level of inflammatory cytokines, particularly IL-6, in the airways and other infected tissues. Several studies have reported the function of the endocannabinoid system in regulating inflammation and different immune responses. Cannabinoids are a class of natural chemicals found in the Cannabis plant. Recently, the anti-inflammatory properties of cannabinoids and their mediatory immunosuppression mechanisms through the endocannabinoid system have engrossed scientists in the health field for infectious conditions. Research suggests that the immune system can regulate cytokine activation through cannabinoid receptors, particularly with Cannabidiol (CBD), the second most prevalent compound in cannabis. While CBD has been deemed safe by the World Health Organization and shows no signs of abuse potential, excessive CBD use may lead to respiratory depression. CBD shows promise in reducing immune cell recruitment and cytokine storms in organs affected by SARS-CoV2. However, before clinical use, it’s crucial to evaluate cannabinoid-based medications’ active ingredient concentrations and potential interactions with other drugs, along with associated side effects. Indication-based dosing, consistent formulations, and ensuring purity and potency are essential. This review highlights cannabinoids’ effects on COVID-19 management and prognosis, drawing from preclinical and clinical studies.
... The two most researched cannabinoids are ∆9-tetrahydrocannabinol (∆9-THC), cannabis's primary psychoactive component, and cannabidiol (CBD), a nonpsychoactive component with many hypothesized medical benefits, such as reduced inflammation, antibacterial activity, and analgesia [30]. Numerous studies concluded that THC enhances HSV viral replication [31]. For example, pretreatment of HSV-2-infected cells with micromolar concentrations of ∆9-THC increased the number of infectious virions by 100-fold [80], while others showed that ∆9-THC enhances HSV-2 virion egress, by perturbing the host cell's plasma membrane [31]. ...
... Numerous studies concluded that THC enhances HSV viral replication [31]. For example, pretreatment of HSV-2-infected cells with micromolar concentrations of ∆9-THC increased the number of infectious virions by 100-fold [80], while others showed that ∆9-THC enhances HSV-2 virion egress, by perturbing the host cell's plasma membrane [31]. Cabral et al. also conducted a study in which guinea pigs were administered ∆9-THC, prior to intravaginal introduction of HSV, demonstrating significantly more severe genital disease, higher mean vagina-shed virus titers, and higher mortality, during a 30-day study period, compared to controls, implying that ∆9-THC decreases guinea pig resistance to HSV-2 vaginal infection [32]. ...
... Contrary to these studies, other studies found conflicting evidence of THC's inhibitory effects of THC on HSV-infected human cells. For example, it was found that neither HSV-1 or HSV-2 were replicative or extensively cytopathic to human cell monolayer cultures, where different concentrations of ∆9-THC were introduced before, during, and after HSV infection [31]. THC-mediated inhibition of HSV replication was both time-and dosedependent, and not influenced by the pH of the culture medium, thus suggesting that THC preferentially reduces the infectivity of enveloped HSV [85]. ...
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Herpes simplex virus-1 (HSV-1) and -2 (HSV-2) are large, spherically shaped, double-stranded DNA viruses that coevolved with Homo sapiens for over 300,000 years, having developed numerous immunoevasive mechanisms to survive the lifetime of their human host. Although in the continued absence of an acceptable prophylactic and therapeutic vaccine, approved pharmacologics (e.g., nucleoside analogs) hold benefit against viral outbreaks, while resistance and toxicity limit their universal application. Against these shortcomings, there is a long history of proven and unproven home remedies. With the breadth of purported alternative therapies, patients are exposed to risk of harm without proper information. Here, we examined the shortcomings of the current gold standard HSV therapy, acyclovir, and described several natural products that demonstrated promise in controlling HSV infection, including lemon balm, lysine, propolis, vitamin E, and zinc, while arginine, cannabis, and many other recreational drugs are detrimental. Based on this literature, we offered recommendations regarding the use of such natural products and their further investigation.
... Based on these findings, it has been reported that CBR2 can reduce the immune-induced pathological damage of RSV, which is characterised by severe lower respiratory tract infections, especially in the younger age group, and can be evaluated as a therapeutic agent. (39). ...
... Cannabinoids have the potential to worsen the disease when factors such as HSV-2, Kaposi's sarcoma herpes virus, Vesicular stomatitis virus, HCV, Coxpox, HIV and SIV are encountered and the inflammatory response required for viral clearance and the cell-directed antiviral response are reduced (39,40). Cannabinoids may have the potential to benefit against these diseases when the host inflammatory response is associated with direct pathology rather than recovery when infected with viruses such as Theiler's murine virus, Borna disease virus, HIV, and SIV (40). ...
... Based on these findings, it has been reported that CBR2 can reduce the immune-induced pathological damage of RSV, which is characterised by severe lower respiratory tract infections, especially in the younger age group, and can be evaluated as a therapeutic agent. (39). ...
... Cannabinoids have the potential to worsen the disease when factors such as HSV-2, Kaposi's sarcoma herpes virus, Vesicular stomatitis virus, HCV, Coxpox, HIV and SIV are encountered and the inflammatory response required for viral clearance and the cell-directed antiviral response are reduced (39,40). Cannabinoids may have the potential to benefit against these diseases when the host inflammatory response is associated with direct pathology rather than recovery when infected with viruses such as Theiler's murine virus, Borna disease virus, HIV, and SIV (40). ...
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cannabinoid enfeksiyon
... Cannabinoids have been shown to influence the production and function of acute phase and immune cytokines, as well as the activity of network cells like macrophages and T helper cells, Th1 and Th2. These findings are significant because they demonstrate that cannabis can be immunomodulatory and, in certain circumstances, accelerate disease progression via apoptosis [34]. Defective apoptosis increases the production of pro-inflammatory cytokines, triggering a chain of events that leads to multiorgan failure and death. ...
... Recently several published patents have dealt with the various effects of diverse medicinal plants on including Kalidindi in 2022 [7], Su et al in 2021 [8], Zhong et al. in 2008 [9], Al Jasim et al in 2022 [10] were able to invent methods for treatment, prevention, and protection against viral infections, including coronavirus infection and symptoms like COVID-19, by using several of medicinal plants extract. Based on the previous studies, the natural compounds, particularly secondary compounds isolated from medicinal plants such as five metabolites of 7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol extracted from Salvia rhytidea, Curcuma zeodaria, Frankincense, Peganum harmala, and Cannabis, respectively, are reliable sources for the development of new drugs on viruses [11][12][13][14][15][16]. ...
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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.
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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.
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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.
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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.
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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.
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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.
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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-