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.

LONG-TERM FLIGHT TO MARS.

• Added: 2015-12-06 T 18:00:43 UTC• DOI: 10.13140/RG.2.1.3142.5363

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.

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)

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.

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.

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.

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.

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.

•

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.

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.

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

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). ”

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.

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”

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).

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.

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.

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”

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.

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. 

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.

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.

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.

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

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.

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.

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 CB1

G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.

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)

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.

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

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.

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.

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.

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.

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

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.

CONCLUSION.

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

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.