Science and Innovation. 2014. V. 10. No. 4. P. 56—68

Chekman1, I.S., Belenichev 2, I.F., Demchenko 2, A.V., Bobrova 3, V.I., Kucherenko1, L.I., Gorchakova 2, N.A., and Bukhtiyarova 2, N.V. 1 O.O. Bogomolets National Medical University, Kyiv 2 Zaporizhia State Medical University, Zaporizhia 3 P.L. Shupyk National Medical Academy of Postgraduate Education, Kyiv IN COMLEX THERAPY OF CHRONIC CEREBRAL ISCHEMIA

The clinical and pharmacological characteristics of nootropics as one of the most effective groups of neuropsychotropic drugs have been considered. The nootropics has been classified by the principal mechanism of action. The examples of clinical use of drugs on patients with chronic cerebral ischemia have been given. Key words: cerebrovascular diseases, cognitive disorders, neuroprotection, and nootropics.

Today, cerebrovascular disease (CVD) is one Chronic cerebral blood circulation failure that of the most important problems of modern medi- in the Soviet literature and clinical practice is re- cine in the view of its widespread occurrence, ferred to «discirculatory encephalopathy» (DE) high mortality or disability caused by it, and sig- has a significant share in the structure of brain nificant financial costs for its treatment and pre- vascular diseases [7]. Discirculatory encephalop- vention [1, 2]. In advanced economies, mortality athy is a syndrome of multiple-lesion brain affec- from cardiovascular diseases continues to range tion as a result of chronic cerebral vascular failure from 12 to 15% of the overall mortality [3]. Ac- and/or repeated episodes of acute cerebrovascu- cording to the statistical forecast, in 2020, it will lar accidents (venous insufficiency, transient reach 25 million cases annually [4]. In Ukraine, ischemic attack, and stroke). The disease is char- CVDs are ranked the second or the third by inci- acterized by a slow progressive course and pro- dence and by mortality among this class of dis- gressive brain function disorder [8]. eases [2]. In 2000—2010, in Ukraine, the number The most common causes of brain circulatory of stroke cases increased 1.6 times, while the total disorders are hypertension, atherosclerosis, cere- number of all CVDs grew from 3.4 to 4.5% [5]. bral arteries, diabetes, and heart disease with a This implies the relevance of pharmacological high risk of thromboembolism into the brain. In correction of cerebral blood circulation failure, as more seldom cases the cerebral circulation disor- well as the importance of means of prevention or ders develop as a result of inflammatory changes in treatment of brain vascular pathology, soma- blood vessels (vasculitis), blood coagulation disor- tovegetative and psychopathologic failures, and ders, abnormalities of vascular development, etc. personal reactions to the disease [6]. In most cases, the cerebral vascular insufficiency develops in the elderly [7, 9]. Stroke and DE can be considered to be two cerebrovascular syn- © CHEKMAN, I.S., BELENICHEV, I.F., DEMCHENKO, A.V., BOBROVA, V.I., KUCHERENKO, L.I., GORCHAKOVA, N.A., dromes which can be a manifestation of the same and BUKHTIYAROVA, N.V., 2014 disease [10]. However, it should be noted that in 56 The World of Innovations most cases, stroke is a result of affection of large of immune changes, and initiation of neuroapop- cerebral arteries (especially, their atherosclerosis), tosis as a consequence of formation of persistent while DE is often caused affection of small cerebral cognitive deficit [21]. vessels (cerebral microangiopathy) [11, 12]. The DE morphological substrate is character- Along with focal neurological symptoms the ized by small focal and diffuse changes in the clinical course of chronic cerebrovascular insuf- white matter of brain, hippocampal sclerosis, as ficiency includes cognitive impairment to which well as by phenomena of secondary cerebral atro- attention has been paid in the last decade because phy [11, 14, 22, and 23]. of its widespread occurrence [13, 14, 15, and 16]. The modern medical science advances thanks In the case of CVS, cognitive impairment has a to the use of new highly effective pharmacologi- progressive character and at some point reaches cal agents having a pronounced therapeutic effect the severity of dementia [13, 17]. Vascular de- of CVD. The introduction of new classes of phar- mentia is one of the most serious complications of macological agents acting at different stages of unfavorable course of cerebral vascular insuffi- pathogenesis and optimizing cerebral metabolism ciency. According to statistics, vascular etiology makes it possible to suspend CVD progression [6, underlies, at least, 10—15% of dementia cases in 24, 25, and 26]. Therefore, the application of neu- the elderly [18]. However, in recent years, on both roprotective agents which combines antioxidant, domestic and foreign publications the emphasis anti-ischemic, and properties are very in clinical research increasingly shifts from iden- relevant [20, 27]. tifying and studying the existing dementia to- The concept of pharmacotherapeutic neuropro- wards the pre-dementia stages of neurogeriatric tection makes it possible to distinguish two main diseases when the therapeutic cure can be more trends. The primary neuroprotection is for inter- effective and able to prevent or significantly defer rupting fast mechanisms of cell necrotic death, i.e. the social maladjustment [19]. the reactions of calcium glutamate cascade (an- Impaired cognitive and associative functions tagonists of NMDA- and AMPA-receptors and under the conditions of cerebral pathologies oc- calcium channel blockers: Remacemide, Rilutek, cur against the background of severe structural Nimotop, etc.) [28]. The secondary neuroprotec- changes of brain cells as a result of inhibition of tion is aimed at reducing the severity of late is- bioenergetic processes, development of glutamate chemia effects: the blockade of pro-inflammatory excitotoxicity, overproduction of reactive oxygen cytokines, adhesion of cell molecules, inhibition of species (ROS), deactivation of antioxidant sys- oxidative stress, normalization of neurometabolic tems, and activation of apoptosis [20]. The energy process, inhibition of apoptosis, and reduction of deficit initiating a glutamate-calcium cascade, i.e. cognitive deficit (antioxidants, antihypoxants, me- the release of aminoacidergic excitatory neuro- tabolitotropic drugs, nootropics: Emoxipin, Thiot- transmitters, aspartate and glutamate, and the riazoline, Glycine, , Thiocetam, Citico- intracellular accumulation of Ca2+ is a trigger link line, Cerebrolysin, Cortexin, Cerebrocurin, etc.) of ischemic death of neuronal cell. The processes [29, 30]. Nootropics are the most important means beginning at the early hours of hemorrhage and of secondary neuroprotection. underlying the glutamate-calcium cascade (chan- Nootropics formed a separate group in the early ges in the metabolism of glutamate and calcium, 1980s, when after successful application of the first oxidative stress, and overproduction of NO•) in- drug in this class, piracetam (nootropil), other duce long-term effects of ischemia. This is a reac- pyrrolidone derivatives appeared. Previo usly, in tion of genome with the launch of genetically the late 1960s, gamma amino butyric acid GA BA programmed molecular mechanisms, dysfunction (Gammalon, Aminalon) was used as a means of of astrocytic and microglial pools, development improving mnemonic processes. According to Science and Innovation. V. 10, no. 4, 2014 57 The World of Innovations

WHO, the group of nootropics includes medicines eral classifications of nootropics. Below, the classifi- that directly activate the cognitive processes, im- cation by the principal mechanism of action is given. prove the memory and mental activity, as well as raise the brain resistance to aggressive factors. CLASSIFICATION OF NOOTROPICS Three decades hence the introduction of neuro- In clinical practice, these drugs are classified tropic drugs into clinical practice for regulation of into two major groups: nootropics of direct ac- memory processes they have become the most tion (cognitive enhancers) and neuroprotective commonly used medical drugs. Moreover, noot- agents [31, 32]: ropics gained a wide popularity not only in neu- I. Cognitive enhancers or «true» nootropics: rology and psychiatry, but also in other areas of 1. Pyrrolidone nootropics () with pre- the hospital and ambulatory pharmacotherapy. dominant metabolite action: Piracetam, Fenotro- Nootropics regulate higher mental processes in pil combined racetams (Thiocetam, Olatropil, and humans, such as cognitive functions and cognitive Phezam). abilities (education) due to modulating the mem- 2. Cholinergic agents: enhancers of synthesis and ory rate and reliability of storage of information release of acetylcholine (Phosphatidylserine, leci- received (introduced). At the same time, they thin, Citicoline); cholinergic receptor agonists (Oxo- change the ability to improve the reproduction tremorine, Bethanechol); and acetylcholines terase of already existing, i.e. stored information, or, inhibitors (Physostigmine, Galantha mine, etc.) conversely, to worsen the extraction of data from 3. Neuropeptides and neurotrophic cerebroprotec- memory and to forget unnecessary information tors: Semax, Cerebrolysin, Cortexin, Cerebrocu rin. (e.g., memories of pain during the surgery, stress- 4. Modulators of glutamatergic system: a) low- ful experiences in disasters, etc.). The modulation affinity NMDA receptor polyamine site antago- of these processes or, in other words, the possibil- nists and partial agonists of AMPA receptors: Me- ity of using pharmacological agents, if necessary, mantine, Ademol); to stimulate or to inhibit the mechanisms of ex- b) AMPA receptor agonists: Nooglutyl; traction of information from short-term and/or c) AMPA receptor partial agonists, as well as en- long-term memory (reproduction of memory en- hancers of noradrenaline and dopamine release: grams) is one of the most important problems of (Ri talin, Donepezil); modern neuropharmacology. A distinctive feature d) NMDA receptor co-agonists: glycine; of nootropics is their ability not to affect the high- e) NMDA mimetics: glutamic acid, D-cycloserine. er nervous activity and the human psyche in its 5. Dopamine receptor agonists: Pronoran; normal (healthy) condition and to improve the 6 GABA receptor agonists: Baclofen. processes in the case of functional disease or mor- II. Neuroprotective agents: phological impairment. Using the present-day 1. Activators of brain metabolism: Mildronat, analytical pharmacological methods it is very dif- Phosphatidylserine, xanthine derivatives of Pen- ficult to establish any significant change in behav- toxifylline, etc. ior of healthy people and animals, as well as in 2. Cerebral vasodilators: Vincamine, Vinpocet- shifts in the conditioned reflex reactions, brain ac- ine, Nicergoline, etc. tivity, or in biochemical processes in the nerve tis- 3. Calcium channel blockers: Nimodipine, Cin- sues under the influence of neuroprotective drugs. narizine, Flunarizine, etc. They have a therapeutic effect of cognition en- 4. Antioxidants: Mexidol, a-tocopheryl acetate, hancers only in the case of mnemonic dysfunc- Thiotriazoline, Emoxipin, Cytoflavin, Glutoxim. tions, if administered, at least, 3—4 months. 5. Substances affecting the GABA system: Ami- The range of modern neuroprotective drugs is la- nalon (Gammalon), Pathogen, Picamilon, Fenib- rge and diversified. In pharmacology, there are sev- ut (Noofen), sodium hydroxybutyrate. 58 Science and Innovation. V. 10, no. 4, 2014 The World of Innovations

6. Different groups of substances: orotic acid, of postsynaptic membrane has been established Naftidrofuryl, ginseng, lemongrass, Ginkgo bi lo- to trigger a gene expression mechanism responsi- ba, and Siberian ginseng. ble for the synthesis of neurotrophins, the nerve For the direct nootropics the effect on memory growth factor (NGF) and the brain derived neu- is the main action, although they have other phar- rotrophic factor (BDNF). For this reason, the macological properties (anticonvulsant, antihy- drugs acting on AMPA receptors can be effective poxic, circulatory, antioxidant, etc.) as well. The as neuroprotective agents. Piracetam, , direct nootropics include substances with very and have been established to activate different structure, from the relatively simple ra- AMPA type of glutamate receptor (the endog- cetams to the complex peptide formations. The enous ligand is amino-3-hydroxy-5-methylisoxa- neuroprotective agents comprise brain metabo- zole-4-propionate). However, they do not affect lism activators, cerebral vasodilators, calcium an- NMDA receptor neurons. This leads to an in- tagonists, antioxidants, and substances affecting crease in the yield of calcium from the cell, as a GABA system. result of which the concentration of intracellular calcium decreases. increases the MECHANISMS OF ACTION OF NOOTROPICS rate of choline sodium-dependent absorption in Two main links can be distinguished in the the hippocampus. It affects the cognitive func- mechanism of action of nootropic drugs: the neu- tions through acceleration of flow of impulses rotransmitter and the metabolic ones. Both from cholinergic neurons in the septum of hip- mechanisms occur in both groups of products, pocampus. has been established but one of them is the dominant mechanism. to have an affinity with H-cholinoreceptors, not Neurotransmitter mechanisms include the ef- with NMDA-subtype of glutamate receptors. fect of the drug on GABA, choline, glutamate, The introduction of the drug increases the dopamine, or glycinergic systems. In this respect, number of both H-cholinoreceptors and NMDA- the most promising are the agonists of NMDA receptors, but decreases the amount of serotonin and AMPA subtypes of glutamine receptors and and dopamine receptors in the brain. Unlike oth- the agonists of GABA receptors (Nooglutyl, Me- er piracetam-like drugs, has a pro- mantine, and Modafinil) which have larger strength nounced anticonvulsant effect, in connection with that the classical racetams (Piracetam, Pramira- which it is used as a cure for epilepsy. Its mecha- cetam, Aniracetam), but these drugs can cause a nism of action has not been fully understood, but number of severe side effects. The substances that it is assumed not to have a direct effect on such can be bound to the AMPA receptors have at- «classic» antiepileptic processes / target as GA- tracted the attention of researchers who deal with BA-ergic transmission and sodium channels. The developing new drugs for the treatment of Alzhe- most probable site of action of Levetiracetam is imer’s and Parkinson’s diseases, schizophrenia, SV2A protein. This protein is assumed is to be in- depression, epilepsy, amyotrophic lateral sclero- volved in the process of exocytosis. As a result of sis, Huntington’s chorea, NPD disease, multiple structural similarity with membrane transporters sclerosis, mild cognitive impairment, and age cog- it can play a role in maintaining synaptic homeos- nitive impairment. Among the various types of tasis of such components as ATP and calcium. ligands of AMPA receptors the positive modula- The effect on calcium homeostasis is supported tors (or potentiators) that improve memory and by the data according to which SV2A interacts cognitive functions in humans and animals are of with synaptotagmin that is a sort of calcium sen- particular interest, insofar as the intense ion cur- sor, as well as by the inhibition, under the action rent caused by the action of these modulators on of Levetiracetam, of calcium release by PC-12 AMPA receptors with subsequent depolarization cells containing SV2A and by the lack of this ef- Science and Innovation. V. 10, no. 4, 2014 59 The World of Innovations fect in SV2A-free 3T3-fibroblasts. According to mate excitatory neurotransmitter into synapse, the available data, within the therapeutic dosage which stimulates the AMPA receptors on the range, Levetiracetam reduces the ion fluxes into neuron surface receiving the nerve signals. The neurons, which are induced by AMPA receptor other surface protein, NMDA receptor, reacts to activation. This effect is likely caused by inhibi- glutamate under the action of depolarization. As tion of calcium channels. Levetiracetam and Ne- a result, a complex chain of molecular interac- firacetam activate NMDA receptors through the tions involving the formation of cyclic AMP and, activation of protein kinase C and the phosphor- consequently, the CREB protein activation, is ac- ylation of one of subunits of this receptor. Conse- tivated inside the cell. The CREB activation is quently, this increases the binding of glycine with crucial for memory consolidation: the activated NMDA receptors. Fasoracetam modulates the glu- CREB helps to «turn on» genes, in particular c- tamate receptors, which leads to adenylate cy- fos, responsible for the synthesis of protein en- clase activation and enhances the formation of hancers of specific synapses [33]. The AMPA mi- cyclic adenosine monophosphate (cAMP) in- metics accelerate the processes of memory by en- volved in various «signalling» processes, includ- hancing the reaction of AMPA receptors to gluta- ing education and memory. mate, i.e. by facilitating the depolarization. These Due to the normalization of energy metabolism drugs cause an increase in the level of active the racetams enhance the release and reuptake of CREB in cells, for example, by suppressing the neurotransmitters (glutamate, norepinephrine, phosphodiesterase destroying the cyclic AMP. dopamine, etc.). The racetams reduce the inten- The formation of memory trace in the cell is ac- sity of lipid oxidative modification reactions and companied by the formation of a mediator mole- formation of free radicals, as well as contribute to cule, the cyclic AMP (cAMP). This molecule their elimination. Also, they can create the condi- stimulates the synthesis of protein binding to the tions for facilitating the synaptic neurotransmit- nerve cell DNA. As a result, a whole set of genes ter mechanisms and for activating the synthesis responsible for the synthesis of proteins complet- of proteins, in particular, S-100 memory protein ing the synapses is activated. Thereby these pro- and RNA. The racetams increase the intensity of teins increase the synapse effectiveness. This pro- incorporation of labeled phosphatidylcholine in- cess underlies the consolidation of memory trace. to protein and uridine into RNA, as well as the The triggering protein is cAMP response element incorporation of P32 into the brain phospholipids, binding protein (CREB). The higher is the CREB which enhances the synthesis of macromolecules level in neuron, the faster is the memory consoli- required for the memory processes. Along with dation. Usually, cyclic AMP in the cell is dest- this, racetams activate adenylate cyclase which royed by phosphodiesterase (PDE). Theoretical- catalyzes ADP transformation into ATP as well ly, the PDE inhibition increases the time of CREB as regulate the glucose utilization in nervous tis- activity and the effectiveness and rate of memory sue and the Na/K-ATPase activity. formation. During preliminary tests, PDE inhibi- Recently, the use of nootropics whose dominant tors have proved themselves to be an effective mechanism of action is the activation of glutamine memory enhancer. Therefore, the pharmaceutical AMPA receptors (ampakines): Nooglutyl, Mema- companies are actively developing PDE-based ntine, Ademol, Modafinil, and Ritalin, has been drugs (known as PDE-4). intensively discussed. This group of drugs acts Among the positive modulators of AMPA re- primarily on two processes developing in the neu- ceptors there Modafinil and Ritalin, drugs that rons during memory consolidation: membrane not only intensify the glutamate transmission, depolarization and CREB protein activation. The but also increase the concentration of noradrena- depolarization occurs after the release of gluta- line and dopamine in the brain tissue. Modafinil 60 Science and Innovation. V. 10, no. 4, 2014 The World of Innovations has not only mnemotropic, but also anti-depres- roplasticity in intact areas thereby facilitating sive, adaptogenic, and narcoleptic effects. Ritalin functional recovery. has similar effects. Clinical trials of Citicoline in acute phase of Among the «true» nootropics there are the ischemic hemorrhage in Spain, Italy, France, Ja- drugs that activate cholinergic transmission, Cit- pan, and the United States have demonstrated icoline (Ceraxon) and Donepezil. Citicoline (also that it facilitates the recovery of neurological known as cytidine 5’-diphosphocholine, CDP- function, as well as reduces the cerebral infarc- choline) is a mononucleotide consisting of ribose, tion in patients with ischemic stroke [35, 36, 37, cytosine, pyrophosphate, and choline. Citicoline 38, 39, and 40]. acts as a donor of choline for the biosynthesis of The ability of Citicoline to enhance cognitive acetylcholine and increases its release in cholin- function in patients with vascular pathology of ergic nerve endings. It enhances attention, capac- the brain has been showed in a number of placebo- ity to education, and memory. Citicoline intensi- controlled studies. One of early tests showed a fies dopamine synthesis, probably due to en- significant enhancement of cognitive functions, hanced activity of tyrosine hydroxylase retarding primarily attention, accompanied by improving the dopamine reuptake in the nerve endings. affective status in 33 patients with vascular de- Both the receptor and the metabotropic mecha- mentia treated with Citicoline at a dose of 1 g/ nisms with nootropic and neuroprotective effect day intravenously for 28 days [41]. A double-blind are typical for citicoline. Citicoline enhances the placebo-controlled study involving 100 patients rapid regeneration of damaged cell surface and with chronic cerebrovascular insufficiency dem- mitochondrial membranes while maintaining the onstrated that being administered at a dose of 1 g/ cell integrity and bioenergetic capacity. Citico- day intravenously Citicoline caused an improve- line reduces the phospholipase content, which ment of cognitive, affective, and behavioral func- prevents apoptotic and necrotic death of neuro- tions [42]. A double-blind placebo-controlled trial cytes. The Citicoline metabolites: choline, me- involving 146 patients with multi-infarct demen- thionine, betaine, and nucleotides derived from tia proved that the administration of Citicoline at cytidine are involved in many metabolic proc- a dose of 750 mg/day intravenously for 2 months esses and regulate the thiol-disulfide equilibrium led to a significant improvement of Mini-Mental of nervous tissue system. Citicoline stabilizes li- State Examination (MMSE) indicators, whereas pid rafts carrying the glutamate transport pro- in the placebo group a slight deterioration is re- teins thereby speeding up the removal of gluta- ported [43]. Interestingly, that the repeated study mate excitotoxic neurotransmitter from the syn- conducted in 10 months demonstrated the sus- aptic cleft. Citicoline enhances phospholipid syn- tainability of obtained results: the state of patients thesis and neuron repair. The preclinical studies who administered Citicoline was stable, whereas demonstrated the efficacy of Citicoline in reduc- the patients receiving placebo continued to dete- ing the severity of ischemic brain affection. Citi- riorate. The ability of Citicoline administered at a coline reduces the severity of apoptosis and de- dose of 1000 mg/day intramuscularly by two generation of hippocampal neurons. It improves courses of 4 weeks to enhance the cognitive and memory in experimental animals [34, 35]: the affective functions has been confirmed in placebo- animals who administered Citicoline in the sub- controlled studies [44]. acute phase of hemorrhage showed better motor Using PET it has been showed that the im- recovery. In the structure of motor neurons, there provement of cognitive function due to adminis- are observed an enhancement of branching of tration of Citicoline in patients with vascular de- dendrites and an increase in the spine density. mentia correlates with increased cerebral per- These data indicate that Citicoline increases neu- fusion [45]. In patients with multi-infarct demen- Science and Innovation. V. 10, no. 4, 2014 61 The World of Innovations tia Citicoline not only improves Mini-Mental Sta te Donepezil (Aricept) is central acetylcholi nes- Examination results, but also reduces the severity terase inhibitor modulating dopamine and gluta- of depression symptoms assessed using the Ham- mate transmission. It is currently approved in the ilton scale [46]. The last conclusion is extremely United States and indicated for suspending the important, given the common post-stroke depres- progressive memory loss in Alzheimer’s disease, sion and its adverse impact on the outcome. The as well as for the treatment of narcolepsy [54]. drug can be effective also at the stage of mild cog- Donepezil is a specific reversible inhibitor of nitive impairment and cognitive deficit related to acetylcholinesterase: it increases the density of n- chronic deteriorative vascular process [47]. Fio- cholinergic receptors in cortex and hippocampus, ravanti and Yanagi [52] in their survey published is an agonist of D2-receptors in cerebral cortex by the Cochrane Library in 2009, proceeding from and a positive modulator of AMPA receptors, im- the analysis of 14 double-blind placebo-control- proves the brain cognitive and integrative activ- led clinical studies conducted since 1978 conclu- ity, facilitates the learning process, enhances met- ded that Citicoline ensured a statistically signifi- al alertness and attentiveness, stimulates the cant moderate mitigation of the severity of cogni- short- and long-term memory. It is regarded as a tive function disorders in patients with cerebrov- promising means of secondary neuroprotection ascular disease, at least, in short-term and medi- for reducing post-shock dysfunction. um-term horizons [48]. In patients with post-stroke The discovery of neurotrophic peptide factors cognitive impairment the long-term treatment led to the formation of a new strategy for pharma- with Citicoline (within 12 months) effectively cotherapy, the peptidergic or neurotrophic treat- improves functional and neurological recovery ment of diseases of the central nervous system. A and facilitates recovery of cognitive functions, es- complex of medical drugs called neurotrophic cer- pecially, orientation in time and attention [49]. ebroprotectors was developed to be used in the The Citicoline favorable effect on cognitive fun- treatment of neurological disorders. Cerebrolysin, ction can be associated with enhanced activity of Cerebrocurin, and Cortexin are the most success- cholinergic system, enhanced synthesis and release fully used drugs for the treatment of neurological of dopamine and norepinephrine in certain brain and psychiatric diseases. The recent studies sho- regions, enhanced phospholipid synthesis and sta- wed the ability of these drugs to interact with re- bilization of cell membranes, and enhanced glucose ceptors via G-protein and to increase the gene uptake by neurons [50]. Using the magnetic reso- expression. The «biologically active conforma- nance spectroscopy it has been showed that the im- tions» have been proposed for them to ensure the provement of cognitive abilities of patients during drug preferable interaction with receptor. treatment with Citicoline correlates with the accu- Neurotrophic cerebroprotectors (Cortexin, Ce- mulation of phosphatidylcholine in the brain [51]. rebrocurin, and Cerebrolysin) reduce the trans- The Cochrane survey [52] covers 14 studies in- mitter dysfunction by increasing the affinity of volving older patients with a variety of disorders, GABA receptors and limiting the hyper-excita- from memory disorders to moderate vascular cog- bility of NMDA receptors. Cerebrocurin and Cor- nitive impairment, diabetes or senile dementia. texin enhance the affinity of BDNF binding to its The authors concluded that the effect of Citico- receptors. The effect of drugs on trkB receptors line on cognitive function was clearly evident at of neurotrophins can indicate that they are in- the behavioral level and it could be easily assessed volved in the regulation of natural growth fac- clinically regardless of paradigm used for the as- tors. The cure of CNS pathologies (cerebral is- sessment. Citicoline is well tolerated, with the che mia, hypertension, alcoholism, and fetal alco- placebo group having showed more side effects hol syndrome) in animals with neurotrophic cer- than the active treatment group [53]. ebroprotector (Cerebrocurin and Cortexin) re- 62 Science and Innovation. V. 10, no. 4, 2014 The World of Innovations sulted in an enhanced expression of c-fos early For the patients who administered Thiocetam, response gene in the hippocampus and sensorim- a decrease in the amount of ischemia-modified otor cortex, against the background of cognitive neurons and slept capillaries and a mitigation of functions recovery. Cerebrocurin shows mitopro- perivascular and pericellular edema were report- tective properties in the case of CNS pathology ed. Decreasing number of slept capillaries is an (cerebral ischemia, hypertension, alcoholism, fetal important pathogenetic factor for the prevention alcohol syndrome) as it mitigates the mitochon- of neuronal death. Thiocetam significantly acti- drial dysfunction and regulates (via HIF-1) the vated the proliferation of glial cells and their activity of cytosolic-mitochondrial compensatory function and caused enhanced satellitosis, which energy shunts. In author’s opinion, the Cerebro- was a major factor in ensuring the livelihoods of curin ability to influence the concentration of HSP neurons during the development of ischemic 70 proteins is a key aspect of the mechanism of its brain damage of any etiology. neuroprotective and nootropic effect. HSPs are As compared with Piracetam, Thiocetam bet- involved in the regulation of CNS cognitive and ter corrects the brain bioenergy deficit in acute mnemonic functions through the chaperone activ- cerebrovascular disorders (stroke), mainly due to ity, i.e. the ability to recognize damaged or newly the recovery of aerobic energy generation. It rais- synthesized memory proteins and to make ATP- es the RNA level in the brain tissues of animals mediated repair of their structure. with stroke, which reflects the activation of pro- Numerous experimental and clinical studies tein synthesis and is an adaptive response to hy- have demonstrated the feasibility of an integrat- poxia, which provides restructuring of brain me- ed drug based on a fixed combination of Pirace- tabolism without increasing oxygen demand. tam and Thiotriazoline and called Thiocetam [55]. Thiocetam’s ability to effect the DNA and RNA Thiocetam as a nootropic drug reduces the co- level, as well as the nuclease activity in the cere- gnitive deficits caused by hypoxia, cerebral ische- brospinal fluid and in the blood has been reported mia, neurotoxins, and alcohol. Thiocetam allevi- for the patients with initial manifestations of cer- ates the mnemonic deficit caused by deprivation ebrovascular disease [56, 58]. of paradoxical phase of sleep and by «conflict sit- Thiocetam inhibits the activity of free radical uation». It significantly surpasses Piracetam by reactions in the ischemic brain, significantly re- the mnemonic strength. duces the accumulation of bio-toxic products (al- Thiocetam has a positive effect on the primary dehydes, ketones) thereby minimizing their neu- processing of information, its fixation and consoli- rodestructive effect on neurons. dation, eliminates the mnemonic deficit not only The researches have shown that Thiocetam be- before the training of animals, but also after it. Pira- ing administered at a dose of 20—30 ml intrave- cetam is effective only at the early stages of memory nously, by drop infusion, in 100 ml of saline solu- formation. Thus, Thiocetam is characterized by a tion 1 time per day facilitates the effective im- wider range of nootropic effects as compared with provement of neuropsychological status, indica- Piracetam [20, 25, 27, 32, 55, 56, and 57]. tors of brain bio electrical activity of in patients The Thiocetam efficacy data are of particular with circulatory encephalopathy (stage II) com- interest for modeling various forms of cerebral plicated with atherosclerosis. ischemia. Thiocetam administered after modeling Thiocetam has a strong antioxidant effect. It acute stroke significantly reduces the inhibition of causes reducing the markers of oxidative and nit- unconditioned reflexes to noxious, photic, and rosating stress (aldehyde phenylhydrazone, car- sound stimuli. It significantly alleviates neurolo- boxyphenylhydrazone, and nitrotyrosine) and the gical disorders and improves motor activity, orien- endothelial dysfunction markers (homocys teine tation, and capacity for training in the animals. and endothelin-1) in parallel with increasing con- Science and Innovation. V. 10, no. 4, 2014 63 The World of Innovations tent of recovered equivalents of thiol-disulfide the synthesis of key antioxidant enzymes, Zn-Cu- system in patients with chronic cerebral ischemia. SOD and Mn-SOD, and the expression of glu- Having been treated, the patients showed signs tathione enzymes. In addition, according to the of improved hemodynamics and alleviated py- results of several researches, which are in good ramidal insufficiency, as well as sensitive and co- agreement with the previous studies of author’s ordination disorders. Among the positive effects team, Cerebrocurin modulates the activity of mi- of treatment with Thiocetam there was also en- tochondrial NO-synthase thereby alleviating the hanced reproduction of visual, auditory, and ver- intensity of nitrosating stress and, consequently, bal stimuli and raised mental capacity. resulting in inhibited neuroapoptosis. Cerebro- curin suppresses all manifestations of apoptosis CEREBROPROTECTORS (ROS production, fragmentation of CA-1 neuron Numerous experimental studies have estab- nucleus in the hippocampus area, and decrease in lished that the neuroprotective and nootropic ef- the number of apoptotic modified cells) and en- fects of Cerebrocurin and Cortexin are based on hances the expression of bc1-2. It surpasses Cor- their ability to mitigate mitochondrial dysfunc- texin, Cerebrolysin, Semax, Noopent, and Pirace- tion and neuroapoptosis of complex pathological tam by the strength of antiapoptotic effect. processes leading to persistent cognitive impair- The experimental studies have showed that the ment. In author’s opinion, the mechanism of an- simulation of CNS pathology followed by cog- tiapoptotic effect of Cerebrocurin is related to its nitive deficit leads to a significant change in the ability to influence the neuron genome in extreme genome response, which manifests itself by viola- condition, namely: Cerebrocurin enhances the ex- tion of the pattern of c-fos early response gene pression of global transcription factor AP-1 and expression (a significant decrease in the number antiapoptotic protein Bcl-2, as well as intensifies of c-fos-positive neurons in the hippocampus and

The mechanism of action of Thiocetam [55]

Properties Pharmacological effects

1. Antioxidant 1. Inhibition of pathways for the formation of reactive oxygen intermediates by neuron bioenergy systems 2. Increased activity of AO enzymes, especially SOD 3. Reduced production of reactive oxygen intermediates in the Fenton and the Haber-Weiss reactions 4. Inhibition of nitrosating stress reactions 5. Increased activity of glutathione component of thiol-disulfide system 2. Anti-ischemic 1. Mitoprotective effect (alleviation of mitochondrial dysfunction) 2. Increase in high-energy phosphates due to ATP synthesis in aerobic reactions 3. Activation of mitochondrial respiratory chain 4. Stimulation of RNA and protein synthesis in ribosomes 5. Enhancement of satellitosis of glial cells 6. Improvement of cerebral hemodynamics 3. Nootropic 1. Inhibition of protein oxidative modification in the brain 2. Improvement of neurocyte trophics 3. Activating effect on GABA shunt 4. Increase in concentration of S-100 4. Antiapoptotic 1. Increase in concentration of antiapoptotic proteins bcl-2 2. Inhibition of NO-dependent mechanisms of apoptosis

64 Science and Innovation. V. 10, no. 4, 2014 The World of Innovations sensorimotor cortex). The changes in the expres- Currently, Cerebrocurin is widely used in clin- sion pattern in the early response gene nucleus, ical practice. Cerebrocurin has been established: «tertiary messengers» (c-fos gene, c-jun gene, krox-  To be an effective therapeutic agent for the 20 gene, zif / 268 gene, etc.) can be considered a treatment of patients with residual effects of genome non-specific response to any noci-influ- stroke (including those who underwent a re- ence, including ischemia. The proteins of fos-, jun-, constructive surgery on the great vessels as a and krox-gene families are known to play a crucial result of stroke), as well as of patients with role in controlling the cell cycle: development, early and moderate chronic DE; growth, and differentiation of cells, as well as to de-  To cause a subject improvement (improvement termine the fate of differentiated neurons and CNS of general condition, enhancement of general cognitive and mnemonic functions. Cerebrocurin motor activity, alleviation and disappearance normalizes the c-fos gene expression. It modulates of headaches and dizziness, pain relief and in- the activity of mitochondrial NO-synthase by miti- crease in range of motion in the paretic limb, gating the nitrosating stress and regulating the mitigation of emotional distress) in the pa- opening of mitochondrial pore and, as a conse- tients with various severity of cerebral vascu- quence, alleviates the mitochondrial dysfunction. lar disease, if administered in the course of pro- Probably, it influences the activity of mitochon- tracted treatment; drial nitroreductase through limiting the forma-  To cause a restitution of pathological neuro- tion of peroxynitrite. In author’s opinion, the Cer- logical symptoms (vasodepression and reduced ebrocurin property to activate the synthesis of spasticity, increased muscle strength and range HSP-proteins is explained, firstly, by its ability to of motion in the paretic limb, reduced anisoco- modulate the genome response under conditions ria, improvement of coordination), if adminis- of hypoxia thereby activating the global transcrip- tered in the course of protracted treatment; tion factors that trigger the HSP synthesis. Sec-  To improve memory, attention, emotional and ondly, several studies have demonstrated the abil- volitional attitude (according to neuropsycho- ity of neurotrophic cerebroprotector (Cerebro- logical studies, for the patients with aphasic curin, Cortexin, and Cerebrolysin) to communi- disorders there were reported an improvement cate directly with HSP-proteins, and to present in spontaneous, interactive, automatic, and re- them as such to dendritic cells. The experimental petitive speech, ability to paraphrase the text, data have allowed the author to suggest that the and capacity of auditory-verbal memory); energotropic effect of Cerebrocurin and Cortexin  To have a positive effect on cerebral hemody- can be realized indirectly via the expression of namics (according to ultrasonography data, HSP-proteins and the activation of enzymes in- the patients with residual effects of stroke and volved in the operation of malate-aspartate shut- DE reported a vasodepression, adequate chan- tle. However, it is necessary to take into account ges in pulse volume, a slight intensification in also the direct ergotropic effect of these drugs re- blood circulation through the main (external lated to their ability to influence the processes of and internal carotid) arteries, a mitigation of mitochondrial dysfunction by inhibiting the open- asymmetry of blood circulation and venous ing of mitochondrial pore and the release of cyto- circulatory distress); chrome C into the cytoplasm, as well as their anti-  To cause a complex restructuring of functional oxidant activity caused by their influence on the systems generating alpha, beta, delta, and theta expression of genes encoding the synthesis of anti- rhythms, which is different for the patients oxidant system enzymes, catalase and superoxide with different types of EEG abnormalities (in- dismutase, and in the case of Cerebrocurin, by its crease in the brain energy, mitigation of patho- influence on the expression of c-fos gene [4]. logical activity, the regulating effect on brain Science and Innovation. V. 10, no. 4, 2014 65 The World of Innovations

rhythm pacemakers at all levels (cortical, cor- the view of the normalization of «target» links of tical-subcortical, and hemodynamic), to create neurometabolism and the inhibition of ischemic a favorable basis for the physical, psychologi- cascade reactions, and at the systemic level, for cal, and social rehabilitation of patients with the mitigation of neurological symptoms and the cerebral vascular pathology, especially, those improvement of CNS cognitive functions. who have suffered stroke);  Not to have side effects; to effect favorably the REFERENCES cerebral hemodynamics and neurometabolism 1. Luschyk, U.B. and Alekseeva, T.S.: Why Do Mortality (due to Cerebrocurin’s neuropsychological fun- and Disease Incidence Related to Cardiovascular Pa- ctions combined with a normalizing effect on thology Not Decline? Practical Angiology, 3 (32), 5—11 liver, lipid and lipoprotein metabolism it is rec- (2010) (in Ukrainian). 2. Mischenko, Т.S.: Epidemiology of Neurological Diseases ommended to be used for the treatment of var- in Ukraine. NeuroNЕWS, 3, 76—77 (2008) (in Ukrainian). ious forms of cerebral vascular disease). 3. Hacke W., Kaste, M., Skyhoi Olsen, T. et al.: Acute Tre- The initial dose of Cerebrocurin shall be, at le- atment of Ischemic Stroke.Cerebrovascular Diseases, 10, ast, 20 ml (10 injections). Intensification of the- 1—11 (2000). rapy in the form of extension of the initial course 4. Netiazhenko, V. and Malchevska, Т.: Anti-Thrombocyte Strategy of Primary and Secondary Prevention of Car- to 15—20 injections and repeated courses are hig- diovascular Accidents (Based on Materials of Consen- hly recommended in the case of severe organic sus on Use of Anti-Thrombocyte Drugs). Medicines of brain pathology, particularly, for the patients who Ukraine, 6, 13—20 (2004) (in Ukrainian). have suffered stroke. 5. Zozulia І.S. and Zozulia, А.І.: Epidemiology of Cereb ro- vascular Diseases in Ukraine. Ukrainian Medical Jour- CONCLUSIONS nal, 5 (85), 38—41 (2011) (in Ukrainian). 6. Moroz, V.А.: Discirculatory Encephalopathy: Modern This paper summarizes the published data on Approach to Treatment and Prevention. Pharmacist. 9, the clinical and pharmacological properties of 20—23 (2008) (in Ukrainian). neuro-psychotropic drugs, the nootropics. Every 7. Mischenko, Т.S., Zdesenko, I.V., Linskaya, А.V., and Mi- year, the wide range of nootropics expands with s chenko, V.N.: New Targets of Therapy in Patients with Chronic Cerebral Ischemia. International Neurological new drugs. This requires that the modern clini- Journal, (40), 7—17 (2011) (in Russian). cian knows of the molecular and biochemical 8. Schmidt, Е.V.: Classification of Vascular Affections of mechanisms and the individual characteristics of Brain and Spinal Cord. Journal of Neurology and Psy- the clinical use of drugs. chiatry, 9, 1281—1288 (1985) (in Russian). The current strategy of the treatment of chron- 9. Damulin, I.V., Parfenov, V.А., Skoromets, А.А., and Ua- ic cerebral ischemia involving nootropics allows khno, N.N. (2003). Blood Circulation Failure in Brain and Spinal Cord. In Yakhno, N.N. (ed.), Neural System for quick and delayed mechanisms of neurode- Disorders: Manual for Therapists. Moscow: Medicine, generation and subsequent cognitive impairment 231—302 (in Russian). and identifies several metabolically achievable 10. Levin, О.S.: Modern Approaches to Diagnostics and goals in the struggle for the survival of neurons Treatment of Discirculatory Encephalopathy. Interna- and enhancement of their functional activity: to tional Neurological Journal, 1(47), 117—124 (2012) (in Russian). normalize the balance of excitatory/inhibitory 11. Pantoni L., Poggesi A., and Inzitari D.: The Relation be- transmitters, to mitigate the mitochondrial dys- tween White Matter Lesions and Cognition. Curr. Opin. function, and to enhance the expression of pro- Neurol. 20, 390—397 (2007). tective proteins. 12. Roman, G.C., Erkinjuntti, T., Wallin, A. et al.: Subcorti- Therefore, it is necessary to include nootrop- cal Ischemic Vascular Dementia. Lancet Neurology, 1, 426—436 (2002). ics, on the differentiated basis, at each subsequent 13. Zakharov, V.V. and Yakhno, N.N.: Treatment of Mild and stage of complex therapy of chronic cerebral is- Moderate Cognitive Disorders. Russian Medical Jour- chemia allowing for their mechanisms of action in nal, 10, 797—801 (2007) (in Russian). 66 Science and Innovation. V. 10, no. 4, 2014 The World of Innovations

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