Indolizidine alkaloids are also known as active biotoxins. Swansonine is especially cited in literature as a cause of locoism. This is a neurological lesion, especially in horses, cattle and sheep508. According to Elbein and Molyneux509 swansonine is toxic due to the imbibition of a-mannosidase, an enzyme needed for proper functioning of mammalian cells. It is also known that swansonine inhibits several hydrolases. In addition, Astragalus lentiginous produces lentiginosine, which is an alkaloid related to swansonine510. It is known as a good inhibitor of several a-glucosidases. This is due to the suppression of digestive enzymes471.
All alkaloids are neurotransmitters and active agents in the nervous system. Many alkaloids from natural plants and also modified alkaloids can impress euphoric, psychomimetic and hallucinogenic properties on humans. Some of them can influence narcosis, states of stupor, unconsciousness, or arrested activity. Some of them in moderate doses dull the senses, relieve pain and induce sleep. In excessive doses they can cause stupor, coma or convulsions. They are known as "narcotics", a term derived from the narcoticus in Latin, narkotics in Greek and narcotique in French. In the 1920s, lysergic acid diethylamide (LSD) was developed on the structural basis of ergotamine, the alkaloid produced by the fungus Claviceps purpurea living with rye (Secale cereale L.). Lysergic acid diethylamide has been developed and used primarily for treatment of schizophrenia. This compound is hallucinogenic. In the small doses it causes psychedelic effects. It is for this reason LSD has been and is used as a narcotic.
Narcotics (Figure 90) are stimulants which are active on the central nervous system causing disorders and some temporary or permanent changes in this system and behaviour. Serious negative consequences of narcotics include dependence, a chronic disorder.
The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentanil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise.
The natural source of these narcotics is Papaver somniferum L. and papaveretum, a mixture of purified opium alkaloids. Papaveretum is approximately 85.5% morphine, 8% codeine and 6.5% papaverine. Only purified alkaloids are considered here, as the total alkaloid content of ripe poppy capsules is only 0.5%. It is recovered from the ripening capsule of papaver when it is in the process of changing colour from blue-green to yellow. When the tubs are cut, it is possible to procure the milk. During coagulation, the milk's colour changes to brown. Fresh opium is soft but it hardens during storage.
Crude opium has been used in the past as a sleep-inducer and in folk medicine for many purposes and smoked for the feeling of pleasure. The last use has lead to drug dependence and unpleasant withdrawal symptoms.
Cocaine h^ h
Morphine h3c °
Apomorphine h3c ; h
Dextromethorphan o o o o o
Figure 90. (Continued)
Narcotics are reportedly among the most widely abused substances in the world, particularly the CNS stimulants cocaine and methamphetamine511. These narcotics are a very serious problem because they may lead to strong drug dependence. Possible treatments for this dependence are relatively difficult. Common ones are based on the so-called "dopamine hypothesis", according to which stimulants have the ability to increase extracellular dopamine, which has an additional narcotic effect511'512'513'514. Cocaine has similar affinity for the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT)515. Narcotic dependence can be treated with the use of the synthetic compounds, chemically similar to narcotic. Dependence, therefore, is a very serious problem. Although there are new findings that indicate k opioid receptors may be involved in the modulation of some abuse-related effects and dopamine levels, problem-free therapy exists only in an optimistic future. It is known that the administration of cocaine upregulates k opioid receptors516,517,518,519. However, k opioid receptor agonists offer an indirect possibility to modulate some of the abuse-related effects of narcotics. Presently, more research is needed on this subject.
Humans have known of and used opium for nearly 5000 years, mainly for medical purposes. Its abuse has been around as long. Governmental and international laws and licences regulate the production of P. somniferum, and only the clinical use of narcotics is legal and reasonable.
As has been stated in this book, alkaloids are special secondary compounds. This is due to a general metabolic dependence on the genetic code and their expression through both the genetic code and metabolic scale mediated by growing factors. It is known that alkaloids can interact with DNA or DNA-processing enzymes and can inhibit protein synthesis, as has been mentioned in this book when referring to bioactivity. Moreover, alkaloids can influence electron chains in metabolism and can modulate enzyme activity. As has been presented, these compounds are biologically very active. Another important role alkaloids play is in the immune systems of living organisms. The amount of empirical research on this role is scant.
Immunity is here defined as the ability to resist infections. Infections caused by micro-organisms can be avoided in many ways. There are external and internal barriers to possible infections. The external barriers are skin (impermeable to many infectious agents), cuticles, skin secretions and pH-value and washing. The internal barrier to infection is namely phagocytosis, a process of killing the infectious micro-organisms by special cells. This ability, first discovered by Metchnikov in Russia in the 1880s, is the basis for immune systems in living organisms.
Immune systems in animals and plants are quite different. There are two types of immune systems in animals: (1) innate, so-called "non-specific" or passive immunity; (2) adaptive, so-called "specifically acquired", active, or cellmediated immunity. Innate immunity is based on barriers to infectious agents and adaptive immunity is based on multiplicative and specific antibody release after contact with an antigen (infectious agent). The so-called "memory cells" in animals respond to secondary contact with an antigen.
Immune systems in plants are based on passive, structural immunity, such as a waxy surface or cuticle, and active immunity exists in the expression of some chemicals. The mechanism of this system is to prevent infectious agents from gaining access to plant cells. Plant immunity may also be protoplasmic. This means that the protoplast in cells is an unfavourable environment for pathogenic development. Plants do not, however, produce antibodies like animals do. The protoplasmic immunity is arranged generally by phytoalexins, non-specific compounds whose concentrations increase in response to infections. Some alkaloids may act in a similar way to phytoalexins or in the direct chemical prevention of the infectious agent its growth520.
Although there are many differences between immunity systems in plants and animals, there are similarities. Both systems have two kinds of immunity: passive and active. Alkaloids may take part in both systems.
Many recent studies have proved that many alkaloids have antiviral properties. This is directly connected with the immune systems of organisms. It is known that the surfaces of viruses contain haemagglutinin, which helps adhering to cells prior to the infection520. It is also known that viruses continually change the structure of their surface antigens through processes of antigenic drift and antigenic shift. Drift is a mutation in the viral genome and the shift process is the change of a virus in the host. These processes lead to alterations in haemagglutinin. Infection can occur only when alterations in haemagglutinin are sufficient to render previous immunity ineffective. The potential role of alkaloids becomes apparent in this stage. These compounds break the alterations in the haemagglutinin. Moreover, alkaloids strengthen antiviral cytotoxic T-cells. Viruses normally work to inhibit these cells by haemagglutinin. Alkaloids seem to benefit the immune system when they decrease haemagglutinin's ability to alter, and furthermore when they strengthen and protect T-cells. CD8+T cells have an especially crucial role in an organism's pathogenic resistance521. These cells can kill malignant cells. Moreover, it is stated that some critical functions of these CD8+T cells depend on helper activity provided by CD4+T cells. The cooperation of these immunity cells subsets involves recognition of antigens521. Some alkaloids may weaken antigens and malignant cells. It is also known that NK cells are cytotoxic to cells infected with viruses520. In the immune system, the interaction between protective cells and chemicals is constant.
T-cells also have a very important role in antifungal activity. Fungal infections are very serious problems for many organisms. Fungi try to go across passive immune systems, in which some alkaloids are also important. Many alkaloids have fungistatic properties. In the defence process, the T cells and the NK cells are very important, because they are cytotoxic to fungi. The influence of alkaloids on fungi is evident in the reduction of their growth and in the advancement of T and NK cells.
Bacterial infections are problematic for many organisms, both animals and plants, because bacteria physiologically try to avoid phagocytosis by surrounding themselves with capsules. Capsule bacteria excrete exotoxins meant to kill phagocytes and destroy the immune system. Antibody defence neutralizes the toxins. Bacteria growing in intracellular spaces are killed by cell-mediated immunity (CMI) through specific synthesis of T cell helpers, which powerfully activate the formation of nitritic oxide (NO-), reactive oxygen intermolecules (ROI) and other microbicidal mechanisms. The role of the alkaloids is in the prevention of bacterial growth and replication. Therefore, alkaloids help immune system activity.
The biological activity of alkaloids against parasites has been mentioned. Many authors have reported on this kind of activity. There are a lot of parasites that cause infections and resulting diseases. One group of these parasites is protozoa. Malaria, as previously mentioned, is caused by the protozoan Plasmodium spp. (Plasmodium vivax, P. falciparum, Plasmodium ovale, Plasmodium malariae). Leishmaniasis (Tropical sare, Kala azar, Espundia) is caused by Leishmania spp. (Leishmania tropica, L. donovani, Leishmania brazilensis). Chagas's disease results from infection by Trypanosama cruzi and sleeping sickness by Trypanosama rhodesiense and Trypanosama gambiense. Helminths and trematodes (flukes) make up another group of protozoa and cause the schistosomiasis. This disease results from infection by Schistosoma mansoni, Schistosoma haematobium and Schistosoma japonicum. Nematodes (roundworms) make up a third group and cause the diseases trichinosis (Trichinella spiralis), hookworm (Straongyloides duodenale, Necator americanus) and filar-iasis (Wuchereria bancrofti, Onchocerca volvulus). These three groups of parasites are especially connected to infections in humans and animals. In the case of plants there are many parasites in the form of micro-organisms and nema-todes. There is large diversity among these parasites. In the steppe grasslands in Eastern Austria, 58 nematode genera were found, including the dominating species Acrobeloides, Anaplectus, Heterocephalobus, Prismatolaimus, Aphelen-choides, Aphelenchus, Tylenchus and Pratylenchus522. Moreover, an average of two to six individuals lived in one gram of soil. Although Zolda's522 study found the plant-feeding nematodes to be third in numeral comparison (after the bacterial- and fungal-feeding), this group of nematodes is known to stress plants. Moreover, recent studies demonstrate that important linkages exist between dwarf mistletoe infection, host plant vigour and the ectomycorhizal colonisation and fungal community composition of pinyon pine (Pinus edulis)523. This study demonstrated that high levels of dwarf mistletoe infection were not associated with an increased mortality of infected trees. The infected trees only showed lower shoot growth. This is a good example of both plant adaptation to parasites and also indirectly of the immune system of the trees. Plant immunity seems to be imperfect, because parasites did establish infections in cells. The reduced growth of shoots was a means of preventing cell death. However, it is necessary to mention the numerous amounts of species of micro-organisms that have intimate, beneficial and sometimes essential relationships. Only a small fraction of these organisms are harmful. Therefore, the action of alkaloids as possible part of plant immunity is connected with strong selectivity and specifics. Although parasites live in the host organism and generally impart no benefits to the host, they have little or no harmful effects on the host in some cases, and their presence may be unapparent. However, micro-organisms that do damage host organism are pathogens. Pathogens and pests should be foremost considered when addressing the potential influence of alkaloids on the immune systems of plants. However, it is known that Cuscuta reflexa and Cuscuta platyloba parasitize Berberis vulgaris but not Mahonia aquifolium. Moreover, Cascuta reflexa parasitized Datura arborea but not Datura stramonium524. The alkaloid patterns in Berberis and Mahonia are similar but not identical. The same can be stated in the case of D. arborea and D. stramonium. Quinolizidine, pyrrolizidine and indole alkaloids are known to have toxic, repellent, deterrent, neutral and stimulating activities depending on the specific aphid-plant relations525. The alkaloid gramine taken from Hordeum is recognized as a chemical that disturbs the feeding activities of cereal aphids.
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