This document discusses acute cerebrovascular radiation syndrome associated with long-term space flight to Mars. It describes the potential risks of radiation exposure during space travel, including the development of radiation neurotoxins that can disrupt the blood-brain barrier and blood flow. It then presents a grading system for acute cerebrovascular radiation syndrome based on neurological symptoms. Finally, it discusses the roles of cannabinoids and their receptors in potentially helping to prevent or treat the biological effects of radiation exposure.

1. PROPHYLAXIS AND TREATMENT OF ACUTE
TOXIC RADIATION CEREBROVASCULAR
SYNDROME ASSOCIATED WITH LONG-TERM
SPACE FLIGHT TO MARS.
DMITRI POPOV. PHD. RADIOBIOLOGY. ADVANCED MEDICAL
TECHNOLOGY AND SYSTEMS INC. CANADA.

2. LONG-TERM FLIGHT TO MARS.
• Added: 2015-12-06 T 18:00:43 UTC
• DOI: 10.13140/RG.2.1.3142.5363

3. LONG-TERM SPACE FLIGHT TO MARS.
• Long-term space flight to Mars.
• Acute Cerebrovascular Radiation Syndrome.
• Neuro-immune post-radiation reactions.
• Role of cannabinoids in prophylaxis and treatment of
biological sequelae of radiation exposure.

4. LONG TERM FLIGHT TO MARS.
• Earth’s biggest source of radiation is the Sun. The Sun emits all wavelengths
in the electromagnetic spectrum. The majority is in the form of visible,
infrared, and ultraviolet radiation (UV). Occasionally, giant explosions called
solar flares and coronal mass ejections (CME) occur on the surface of the
Sun and release massive amounts of energy out into space in the form of x-
rays, gamma rays, and streams of protons and electrons called solar particle
events (SPE).5 A robotic spacecraft called the Solar and Heliospheric
Observatory (SOHO) captured an erupting CME from the surface of the Sun
in the image in figure 46. Note the Earth inset at the approximate scale of
the image. These CME can have serious consequences on astronauts and
their equipment, even at locations that are far from the Sun. (NASA)

5. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• To review the role of Radiation Neurotoxins in triggering, developing
of radiation induced central nervous system injury. Radiation
Neurotoxins – rapidly acting blood toxic lethal agent, which
concentrated, circulated in interstitial fluid, lymph, blood with
interactions with cell membranes, receptors and cell compartments.
Radiation Neurotoxins – biological molecules with high enzymatic
activity and activated after irradiation. The Radiation Neurotoxins
induce increased permeability of blood vessels, disruption of the
blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier and
developing severe disorder of blood macro- and micro-circulation.

6. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• In our experiments Principles of Radiation Psycho-neuro-
immunology and Psycho-neuro-allergology were applied for
determination of pathological processes developed after
irradiation or selective administration of Radiation Neurotoxins
to radiation naïve mammals.

7. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• Neurotoxins was used for study of methods of immune-
prophylaxis and immune-protection against ϒ radiation, Heavy
Ion, Neutron irradiation, Proton irradiation.

8. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• Grading System of Acute Cerebrovascular Radiation Syndrome based on
psycho-neurological signs and symptoms .
• Mild Grade of Cv ARS.
• Mild Psycho-neuroimmunological, psycho-neuro-immunotoxic symptoms.
• Single subjective symptoms: possible anxiety, fatigue, weakness or
headache. The principal effectors of radiation induced activation of
Sympathetic Nervous System and Hypothalamic-Pituitary-Adrenal axis.
Disrupting balance between inhibitory and excitatory neurotransmitters.

9. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• Moderate Grade of Cv ARS.
• Moderate Psycho-neuro-immunological, psycho-neuro-immuno-toxic symptoms.
• Multiple subjective symptoms: anxiety,
• fatigue, weakness and/or headache.
• Edema of brain structures. Inhibitory
• and excitatory neurotransmitters counteractions. Radiation exposure change the balance
and increasing functions of excitatory neurotransmitters – glutamate and aspartate and
decrease functions of inhibitory neurotransmitters – GABA, glycine, adenosine.
•

10. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• Severe Grade of CV ARS.
• Severe Psycho-neuro-immunological, psycho-neuro-immuno-toxic
symptoms.
• Multiple subjective symptoms: anxiety,
• fatigue, weakness and/or headache. Hypotension.
• Fever, mild confusion.
• Disruption of blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier,
developing severe disorder of blood macro- and micro-circulation.

11. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES)
• Extremely severe Grade of CV ARS.
• Extremely severe Psycho-neuro-immunological symptoms,
psycho-neuro-immuno-toxic symptoms. Intra-cortical, intra-
parenchemal bleeding. Severe disruption of blood-brain
barrier, blood-cerebrospinal fluid (CSF) barrier and developing
severe disorder of blood macro- and micro-circulation. Shock.

12. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “The current challenges of modern radiobiology and radiation protection, which
include radiation accidents at nuclear reactors, radiological terrorist attacks
using a radiation dispersal device (RDD), the so-called “dirty bomb”, and
radiation exposure during space flights, present two very important issues. The
first is whether low doses of ionizing radiation have any harmful influence on
human health at all, and the second is the acute and still open for more than a
century discussion of the radiosensitivity/radioresistance of the brain.”
• K. Loganovsky
• Dept of Radiation Psychoneurology, Institute for Clinical Radiology, State
Institution “Research Centre for Radiation Medicine of Academy of Medical
Sciences of Ukraine

13. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “According to the classical foundation of cancer radiotherapy by French radiobiologists
Bergonie and Tribondeau (1906), “The sensitivity of cells to irradiation is in direct
proportion to their reproductive activity and inversely proportional to their degree of
differentiation”. Consequently, the adult nervous tissue was recognized as an excellent
example of a “closed static population”, and, because of its fixed postmitotic state, this
population was considered to be “extremely radioresistant”. At the same time, the
evidence is dramatically increasing in support of the radiosensitivity of the Central
Nervous System CNS (Nyagu & Loganovsky, 1998; Wong & Van der Kogel, 2004;
Gourmelon, Marquette, Agay, Mathieu, & Clarencon, 2005). The development and
validation of biological markers of ionizing radiation is the primary goal of current
radiobiology and radiation protection (Bebeshko, Bazyka, & Loganovsky, 2004). ”

14. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “ Reports about the beneficial health effects of low doses of radiation, as a “radio-
adaptive response”, were widely published (Chen, Luan, Shieh, Chen, Kung, Soong et al.,
2006; Cuttler, 2007; Rodgers & Holmes, 2008). The most conservative threshold of
radiation-induced neuroanatomic changes was assumed to be 2–4 Sv for whole body
irradiation, while that for the CNS was assumed to be 50-100 Gy (Gus’kova & Shakirova,
1989; Gus’kova, 2007). The radiotherapeutic tolerant dose for the brain was assumed to
be 55–65 Gy, and the tolerant fractional dose was assumed to be 2 Gy (Mettler & Upton,
1995). Moreover, a “glial-vascular union” was considered to be the cerebral basis of a
postradiation brain damage, while neurons themselves seemed to be out of this
pathogenesis: consequently, the brain white matter was considered to be much more
radiovulnerable than the brain grey matter.” Loganovsky.

15. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “Sub-chronic exposure with post-accidental (Chernobyl) doses
of 137Cs lead to molecular modifications of pro- and anti-
inflammatory cytokines and NO-ergic pathways in the brain.
This neuro-inflammatory response could contribute to the
electrophysiological and biochemical alterations observed after
chronic exposure to 137Cs (Lestaevel, Grandcolas, Paquet,
Voisin, Aigueperse, & Gourmelon, 2008). Loganovsky”

16. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• Reported earlier that there was prominent impairment of the
left, dominant, cerebral hemisphere functions, especially its
cortico-limbic structures, in children irradiated in utero as a
result of Chernobyl (Loganovskaja & Loganovsky, 1999).

17. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “It is accepted in medical radiology that morphological radiation injuries of the CNS could
arise following local brain irradiation by doses greater than 10–50 Gy. Radiation brain
necrosis was observed at local brain exposure of 70 Gy and more, where the development
of radiogenic dementia was considered to be a possibility. The tolerated dose on the brain
was assumed to be 55–65 Gy and the tolerated fractional dose to be 2 Gy (Gus’kova &
Shakirova, 1989; Gutin, Leibel, & Sheline, 1991; Mettler & Upton, 1995). Primary CNS
damage following total body irradiation were assumed to be at an exposure >100 Gy (the
cerebral form of Acute Radiation Sickness [ARS]) and secondary radiation CNS damage at
an exposure of 50–100 Gy (the toxemic form of ARS) (Gus’kova & Bisogolov, 1971). The
threshold for radiation-induced neuroanatomic changes was assumed to be at the level of
2–4 Gy of whole body irradiation (Gus’kova & Shakirova, 1989, Gus’kova, 2007).”
Loganovski.

18. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “In experimental studies morphological changes of neurons were revealed for as low as
0.25–1 Gy of total irradiation (Alexandrovskaja, 1959; Shabadash, 1964), and a dose of
0.5 Gy has been recognized to be the threshold of radiation injury to the CNS with
primary neuronal damages (Lebedinsky & Nakhilnitzkaja, 1960). Persistent changes in
brain bioelectrical activity occur at thresholds of 0.3 to 1 Gy and increase with the dose
absorbed (Trocherie, Court, Gourmelon, Mestries, Fatome, Pasquier, et al., 1984). These
data suggest that alteration in CNS functioning is likely to occur after relatively low doses
of radiation (Mickley, 1987). It was shown that exposure to ionizing radiation significantly
modifies neurotransmission (Kimeldorf & Hunt, 1965) resulting in multiple effects on the
brain and behavior that depend largely on the dose received (Hunt, 1987). Slowly
progressive CNS radiation sickness has been identified following a single exposure to
total irradiation of 1–6 Gy (Moscalev, 1991)” Loganovski.

19. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• “In the UNSCEAR Report (1982), it was noted that after
exposure to 1–6 Gy, slowly progressive degeneration of brain
cortex develops (Vasculescu, Pasculescu, Papilian, Serban, &
Rusu, 1973).”
• DO LOW DOSES OF IONIZING RADIATION AFFECT THE HUMAN BRAIN?
• K. Loganovsky
• Dept of Radiation Psychoneurology, Institute for Clinical Radiology, State Institution “Research Centre for Radiation
Medicine of Academy of Medical Sciences of Ukraine”

20. ACUTE RADIATION CEREBRO-VASCULAR
SYNDROME. (HIGH DOSES, LOW DOSES).
• Dose thresholds for radiocerebral effects .
• “ADULTHOOD 50−100 Gy Radiation brain damage (o–rthodoxally) >2−4 Sv
Radiation neurological signs (Gus’kova et al.) >1 Sv Neurophysiological,
neuroimaging markers and postradiation cognitive deficit (post radiation
encephalopathy) [RCRM data] >0.3 Sv Neuropsychiatric, neurophysiological,
neuroimmune, neuropsychological, and neuroimaging dose related effects
[RCRM data] >0.15−0.5 Sv Epidemiological data on radiation risks for
cerebrovascular pathology (Ivanov et al, 2006; RCRM data; Shimizu et al.,
1999; Preston et al., 2003)” Loganovski.

21. CANNABINOIDS AND CANNABINOID RECEPTORS.
• The most prevalent psychoactive substances
in cannabis are cannabinoids, most notably THC.
• Tetrahydrocannabinol (THC), or more precisely its main
isomer (−)-trans-Δ9-tetrahydrocannabinol ( (6aR,10aR)-delta-
9-tetrahydrocannabinol), is the
principal psychoactive constituent (or cannabinoid)
of cannabis.

22. CANNABINOIDS AND CANNABINOID RECEPTORS.
• A pharmaceutical formulation of (−)-trans-Δ9-
tetrahydrocannabinol, known by its INN dronabinol, is available
by prescription in the U.S. and Canada under the brand
nameMarinol. An aromatic terpenoid, THC has a very low
solubility in water, but good solubility in most organic solvents,
specifically lipids and alcohols. THC,CBD, CBN, CBC, CBG and
about 80 other molecules make up
the phytocannabinoid family.

23. CANNABINOIDS AND CANNABINOID RECEPTORS.
• Like most pharmacologically-active secondary metabolites of
plants, THC in Cannabis is assumed to be involved in self-
defense, perhaps against herbivores. THC also possesses
high UV-B (280–315 nm) absorption properties, which, it has
been speculated, could protect the plant from harmful UV
radiation exposure.

24. CANNABINOIDS AND CANNABINOID RECEPTORS.
• Pate, David W. (1983). "Possible role of ultraviolet radiation in evolution of
Cannabis chemo types". Economic Botany 37 (4): 396–
405. doi:10.1007/BF02904200.
• Lydon, John; Teramura, Alan H. (1987). "Photochemical decomposition of
cannabidiol in its resin base". Phyto chemistry 26(4): 1216–
1217. doi:10.1016/S0031-9422(00)82388-2.
Lydon J, Teramura AH, Coffman CB (1987). "UV-B radiation effects on
photosynthesis, growth and cannabinoid production of two Cannabis sativa
chemotypes". Photochemistry and Photobiology 46(2): 201–
206. doi:10.1111/j.1751-1097.1987.tb04757.x.PMID 3628508.

25. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• THC, as well as other cannabinoids that contain a phenol
group, possesses mild antioxidant activity sufficient to protect
neurons against oxidative stress, such as that produced
by glutamate-induced excitotoxicity.
• Pertwee RG (2006). "The pharmacology of cannabinoid
receptors and their ligands: An overview". International Journal
of Obesity 30: S13
S18. doi:10.1038/sj.ijo.0803272.PMID 16570099

26. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• THC has mild to moderate analgesic effects, and cannabis can
be used to treat pain by altering transmitter release on dorsal
root ganglion of the spinal cord and in the periaqueductal
gray. Other effects include relaxation, alteration of visual,
auditory, and olfactory senses, fatigue, and appetite
stimulation. THC has marked antiemetic properties. It may
acutely reduce aggression.

27. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• THC appears to result in greater downregulation of cannabinoid
receptors than endocannabinoids, further limiting its efficacy
over other cannabinoids. While tolerance may limit the maximal
effects of certain drugs, evidence suggests that tolerance
develops irregularly for different effects with greater resistance
for primary over side-effects, and may actually serve to
enhance the drug's therapeutic window.

28. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• The actions of THC result from its partial agonist activity at
the cannabinoid receptor CB1 (Ki=10nM[52]), located mainly in
the central nervous system, and the CB2 receptor (Ki=24nM[52]),
mainly expressed in cells of the immune system.[19] The
psychoactive effects of THC are primarily mediated by its
activation of CB1G-protein coupled receptors, which result in a
decrease in the concentration of the second messenger
molecule cAMP through inhibition of adenylate cyclase.

29. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• The presence of these specialized cannabinoid receptors in the brain led
researchers to the discovery of endocannabinoids, such as anandamide and
2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less
selective than endocannabinoid molecules released during retrograde
signaling, as the drug has a relatively low cannabinoid receptor efficacy and
affinity. In populations of low cannabinoid receptor density, THC may act to
antagonize endogenous agonists that possess greater receptor
efficacy.[18] THC is a lipophilic molecule[53] and may bind non-specifically to
a variety of entities in the brain and body, such as adipose tissue (fat)

30. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• The endocannabinoid system (ECS) is a group
of endogenous cannabinoid receptors located in the
mammalian brain and throughout the central and peripheral
nervous systems, consisting of neuromodulatory lipids and
their receptors. Known as "the body’s own cannabinoid
system",[1] the ECS is involved in a variety of physiological
processes including appetite, pain-sensation, mood, and
memory, and in mediating the psychoactive effects of cannabis.

31. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• Two primary endocannabinoid receptors have been identified: CB1,
first cloned in 1990; CB2, cloned in 1993. CB1 receptors are found
predominantly in the brain and nervous system, as well as in
peripheral organs and tissues, and are the main molecular target of
the endocannabinoid ligand (binding molecule), Anandamide, as well
as its mimetic phytocannabinoid, THC. One other main
endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at
both cannabinoid receptors, along with its own mimetic
phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation
of appetite, immune system functions and pain management

32. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• Evidence suggests that endocannabinoids may function as both neuromodulators and
immunomodulators in the immune system. Here, they seem to serve an autoprotective
role to ameliorate muscle spasms, inflammation, and other symptoms of multiple
sclerosis and skeletal muscle spasms. Functionally, the activation of cannabinoid
receptors has been demonstrated to play a role in the activation
of GTPases in macrophages, neutrophils, and BM cells. These receptors have also been
implicated in the proper migration of B cells into the marginal zone (MZ) and the
regulation of healthy IgM levels. Interestingly, some disorders seem to trigger
an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom
relief and inhibition of disease progression, such as in that rodent neuropathic pain
model, where receptors are increased in the spinal cord microglia, dorsal root ganglion,
and thalamic neurons.

33. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• Studies on the effects of marijuana smoking have evolved into
the discovery and description of the endocannabinoid system.
To date, this system is composed of two receptors, CB1 and
CB2, and endogenous ligands including anandamide, 2-
arachidonoyl glycerol, and others. CB1 receptors and ligands
are found in the brain as well as immune and other peripheral
tissues. The cannabinoid system and immune modulation
• Thomas W. Klein1, et al.

34. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS
inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the
cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets.
Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in
cells of the immune system, as well as in brain glial cells. In the present review it is summarized the
effects of cannabinoids on immune reactivity and on the regulation of neuro inflammatory processes
associated with brain disorders with special attention to chronic inflammatory demyelinating diseases
such as multiple sclerosis.
• Mini Rev Med Chem. 2005 Jul;5(7):671-5.
• The role of cannabinoid system on immune modulation: therapeutic implications on CNS
inflammation.
• Correa F et al.

35. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• There is a growing amount of evidence suggesting that
cannabinoids may be radio-protective and radio-
neuroprotective in CNS post-radiation inflammatory conditions.

36. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• CNS Drugs. 2003;17(3):179-202.
• Therapeutic potential of cannabinoids in CNS disease.
• Croxford JL
• Curr Opin Investig Drugs. 2002 Jun;3(6):859-64.
• Cannabinoids in the treatment of pain and spasticity in multiple
sclerosis.
• Smith PF

37. CANNABINOIDS AND CANNABINOID
RECEPTORS.
• Drugs R D. 2003;4(5):306-9.
• Cannabis-based medicines--GW pharmaceuticals: high CBD, high
THC, medicinal cannabis--GW pharmaceuticals, THC:CBD.
• Curr Neuropharmacol. 2006 Jul;4(3):239-57.
• Role of the cannabinoid system in pain control and therapeutic
implications for the management of acute and chronic pain episodes.
• Manzanares J1, Julian M, Carrascosa A.

38. CONCLUSION.
• Medical Management for consideration:
• 1. Antioxidants.
• 2. Pain killers.
• 3. Cannabinoids.
• 4. Immune-prophylaxis and Immune-therapy.

39. CONCLUSION.
• Extremely important and necessary to research, investigate,
integrate international efforts for further comprehensive
development of methods for prevention, protection,
prophylaxis of the negative health effects and the biological
sequelae of exposure to ionizing radiation of humans, in
general, and on the CNS.