Histamine as a cns neurotransmitter

This presentation impart a knowledge about Histamine,receptor,and antagonist.
Recent advances also mentioned like H3 & H4 receptors role in cognitive impairment etc.

1. Seminar On histamine as a CNS Neurotransmittor Presented by Moh.Uzai r M.Pharm(Pharmacology) I st Sem SPER, Jamia Hamdard New Delhi

2. Contents 1. Histamine 1 2. Biosynthesis of Histamine 2 3. Release of Histamine 3-6 4. Histamine Receptors 7 5. Pharmacological Action 8 6. Drugs acts on H 1 Receptor 17 a. First Generation 18 b. Second Generation 19-20 c. Third Generation 21 7. Drugs acts on H 2 Receptor 24-33

3. Contd… 8. Drugs acts on H 3 Receptor & role in Neuro- Disease 34-50 a. Schizophrenia b. Alzheimer Disease c. Addiction d. ADHD 9. H 4 Receptor 51 10. References 52-53 3

4. 1.Histamine (TISSUE AMINE) Histamine is found in most tissues and released by mast cells. Released during inflammatory or allergic reaction. Synthesized from Histidine. Act as autacoids means secreted locally to decrease & increase the activity of nearby cells. 1

5. 2.Biosynthesis of Histamine 2

6. 3.Release of Histamine The release of histamine from tissues is caused by the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. Allergies, anaphylaxis can also trigger release of histamine. 3

7. In mast cells, histamine is stored in granules as an inactive complex. Inactive complex composed of histamine and the polysulfated anion, heparin,along with anionic protein. Histamine is also known as a neuromodulator, since it regulates the release of other neurotransmitter, like acetylcholine, norepinephrine , and serotonin. 4

8. Histamine also has presynaptic receptor(H 3 ) inhibit the release of histamine. Inverse agonist or antagonist of this receptors may increase histamine leading to wakefulness and decrease appetite(induces anorexia). Pitolisant (tiprolisant) drug approved for Narcolepsy. Ciproxifan drugs antagonist, showing an exclusively high species-specific affinity at rodent compared to human H 3 receptor. 5

9. It is well studied as reference compound for H 3 receptor in rodent models for neurological diseases connected with neurotransmitter dysregulation , e.g. attention deficit hyperactivity disorder or Alzheimer’s disease. 6

10. Postsynaptic Gq = ↑Ca ++ . BV = Ca ++ dependent NO release = V.D . Hypothalamus Postsynaptic Gs = ↑CycAmp . Stomach = ↑Hcl . Heart ↑Contraction ↑HR ↑Wakefulness ↓Appetite . B.V = V.D Presynaptic Gi = ↓CycAmp ↓Histamine release H 1 H 2 ↓Effect Leukocytes Gi = ↓CycAmp Chemotaxis 7

11. Pharmacological Action Nervous System Histamine is a powerful stimulant of sensory nerve endings may results in pain and pruritis(itching). This above results produced by H 1 receptor, is important component of urticarial response to insect bites and stings. Histamine is powerful contractor of visceral smooth muscles through H 1 receptors and results in bronchoconstriction and abdominal cramps. 8

12. Glands Histamine increases gastric secretion by stimulation of H 2 receptor. This action is exerted directly on parietal cells and mediated by increased cAMP generation and results in turn activates the membrane proton pump (H + , K + ATPase) 9

13. Autonomic ganglia and adrenal medulla These are stimulated and release of Adrenaline occurs, which can cause a secondary rise in BP. CNS The histaminergic neurons originate from the tuberomammillary nucleus ( TMN ) of the posterior hypothalamus & send projections to most parts of the brain Histamine does not penetrate blood brain barrier- no central effects are produced on i.v. injection. Intracerebroventricular administration produces rise in BP, cardiac stimulation, behavioral arousal, hypothermia, vomiting and ADH release 10

14. The TMN of the hypothalamus is the sole source of histaminergic innervations of the CNS. The most densely innervated target of the histaminergic neurons in the Hypothalamus. 14

15. Histaminergic TMN neurons are active during wakefulness and exert multiple functions.(thus can be used to treat sleep-wake disorders, like narcolepsy , via modulation of H3 receptor function.) 12

16. Blood vessel Histamine causes dilation of small blood vessels and can results in flushing and hypotension. Fall in blood pressure is mediated by both H 1 ( early; by release of NO ) as well as H 2 ( delayed and persistent; direct actions on smooth muscles of blood vessels ) receptors. Increases the capillary permeability and results in exudation of plasma(edema) due to separation of endothelial cells. 13

17. Triple response Intradermal injection of histamine may results in 1. Red reaction/Flush( due to vasodilation ) 2. Wheal/formation of oedematous patch( exudation of fluid due to increased permeability ) 3. Flare/Red irregular surrounding the wheal( spreading redness due to axon reflex ) It is primarily an H 1 response. 14

18. Heart/Cardiovascular system H 1 receptor stimulation has negative dromotropic ( decreased AV conduction ) on isolated heart. H 2 receptor stimulation increases the force of contraction on isolated heart. Effect on intact heart is not prominent means d irect effects of histamine on in situ heart are not prominent. 15

19. 5.Drugs acts on H 1 Receptor These drugs act as competitive antagonist. Classified into first generation & second generation compounds on the basis of CNS penetration and anticholinergic properties. First Gen drugs are highly lipid soluble, cross the BBB and hence cause sedation & psychomotor impairment. C/I in persons requiring constant attention , children and elderly(>65 years). 17

20. Highly Sedating Diphendydramine Promethazine Hydroxyzine Doxepine Pheniramine Cyprohepatadine Meclizine Cinnarizine Chlorpheniramine Mepyramine Cyclizine Clemastine 18

21. Uses Of First Gen H 1 Blockers Based On H 1 blocking action Allergic condition like itching, urticaria, hay fever etc. Insect bite, ivy poisoning and to prevent adverse effects due to histamine releasers. Based On Anticholinergic properties Common cold(to control rhinorrhoea) Motion sickness(as prophylactic agent) Parkinsonism(Promethazine may be used) Acute muscular dystonia 19

22. Other Uses Antihistaminics are drug of choice for idiopathic pruritis. Cinnarizine is used in vertigo 20

23. b.Second Generation Drugs These drugs are less lipid soluble, don’t cross BBB and hence are nonsedating. Preferred in persons requiring constant attention. E.g. Truck drivers etc. More potent and more efficacious than first generation. Long acting as compared to first generation. All second generation antihistaminics are metabolized to active products except cetrizine and mezolastine. 21

24. Second generation Drugs Systemic Topical Cetrizine Loratadine Rupatadine Terfenadine Astemizole Acrivastine Azelastine Olopatadine Ketotifen Alcaftadine Bepotastatine Emedastatin Epinastine Levocarbastine 22

25. c.Third Generation Drugs Some authorities describe the term 3 rd generation antihistaminics which are derivatives of the second generation. Examples- Levocetrizine Desloratadine Fexofenadine 23

26. H 2 Blockers These drugs competitively inhibit H 2 receptors in parietal cells, thus inhibiting the acid secretion. ACh and gastrin act partly by causing the release of histamine, therefore acid secreting capacity of these agents also is decreased by H 2 blockers. Histamine is primarily responsible for nocturnal acid secretion, which is inhibited by H 2 blockers. 24

27. Examples Cimetidine Ranitidine Famotidine Roxatidine Nizatidine Loxatidine These drugs are used for peptic ulcer, Zollinger - Ellison syndrome and gastro esophageal reflux disease(GERD). 25

28. Cimetidine is not used routinely because: It can cross blood brain barrier and result in mental state changes. It inhibits binding of dihydrotestosterone to androgen receptors that can manifest as impotence in males. It inhibits metabolism of estradiol and increases serum prolactin levels on long term use, thus can cause gynaecomastia (in males) and galactorrhoea (in females). 26

29. It is a potent inhibitor of CYP enzymes and can increase plasma concentration of warfarin, theophylline and many other drugs. It is the least potent H 2 blocker. Ranitidine recently banned in India due to contamination by cancer causing substance NDMA( N-nitrosodimethylamine). 27

30. 28 The metabolic degradation of NDMA produces formaldehyde and methanol, and the alkylating intermediate reacts with nucleic acids and proteins to form methylated macromolecules called as O 6 -methylguanine as the likely proximal carcinogenic agent. Pathogenesis Of NDMA Induced Hepatic Carcinoma

31. Methanol and Formeldihyde are highly toxic to liver and initiates severe inflammation and confluent hemorrhagic necrosis.  These processes results in extreme oxidative stress and production of reactive oxygen species (ROS) that further contributes to hepatocyte damage and necrosis. Furthermore, NDMA decreases catalase and glutathione peroxidase, the major antioxidant enzymes present in the liver. 29

32. NDMA decreases serum and liver concentrations of ascorbic acid, another major antioxidant. The persistent treatment of NDMA further increases oxidative stress and lipid peroxidation that enhances hemorrhagic necrosis and collapse of liver parenchyma. The extensive panlobular and multilobular necrosis lead to massive hepatic necrosis, which in turn initiates mitosis and hepatic regeneration. 30

33.  On the other hand, the resting HSCs(Hepatic Stellets Cells) transform into myofibroblast like cells and start extensive synthesis of connective tissue proteins. This causes deposition of mature collagen fibrils in the extracellular matrix of the liver and results in hepatic fibrosis. All these processes lead to condensation of hepatic reticulin framework, production of granulation tissue, and ultimately scar formation. 31

34. The ischemic consequences of the hepatic tissue and confluent necrosis amplify the process of nodular regeneration and drive towards to liver cirrhosis. The repeated tissue repair and regeneration process can lead to aberrations and mutations in genes and end up in development of HCC( Hepatocellular carcinoma). Alternatively, the methyl carbonium ions produced during metabolic degradation of NDMA methylate the hepatocyte DNA that results in gene mutation and trigger HCC. 32

35. 33 The metabolic activation and detoxification of NDMA cause hepatocyte injury, inflammation, neutrophilic infiltration, and massive hepatic necrosis, which results in oxidative stress and production of reactive oxygen species. These processes induce activation of hepatic stellate cells and increased synthesis of connective tissue components, especially collagens that end up in hepatic fibrosis. The chronic liver injury and perpetual fibrosis lead to liver cirrhosis, which could develop into hepatocellular carcinoma

36. H 3 Antagonist Histamine H3 receptor (H 3 R) antagonists/inverse agonists have revealed potential to treat diverse disease states of the central nervous system (CNS) including Alzheimer’s disease (AD), attention-deficit hyperactivity syndrome (ADHD), schizophrenia, obesity, pain, epilepsy, narcolepsy, substance abuse, etc 34

37. Alzheimer Disease AD is a chronic and progressive neurodegenerative brain disease. In AD the histamine production is diminished but in early stage histamine production is paralleled by build up of neurofibrillary tangles (NFT) in the Tuberomammillary Neuron. A significant loss of large-sized histamine containing neurons in the rostral TMN was observed where numerous NFT were found, indicative of a central histaminergic dysfunction. 35

38. Central histaminergic fibres originating from the TMN in the posterior hypothalamus widely projects into different brain areas including the cerebral cortex, thalamus, basal ganglia, amygdala, and hippocampus, where histamine is crucially associated with a large number of basic physiological functions including sensory and motor functions, cognition, attention, learning, and memory. 36

39. Blockade of human H3 autoreceptor by Thioperamide evokes the increase of the neuronal histamine release. The neurotransmitter modulates cognition processes via both human H1 and H2 receptors or via cholinergic and GABAergic interneurons either directly via excitation of neocortical pyramidal neurons and thalamic relay neurons or indirectly via excitation of ascending cholinergic neurons.

40. Amyloid plaque, consisting of extracellular deposits of β -amyloid protein in selective areas of brain such as cortex, hippocampus, amygdala and subcortical nuclei etc. Neurotoxicity in AD results from excessive formation of A β protein. Familial AD(rare) results from mutations in the genes for amyloid precursor protein(APP) which causes an increase in A β formation. 38

41. NFT arising from hyperphosphorylation of tau, a microtubule-associated protein. Activation of cellular path- ways that inhibit tau kinase signaling and subsequent tau hyper- phosphorylation is considered to be the most feasible strategy to prevent tau aggregation and associated pathological effects. Suppression of tau protein can also block A β- induced apoptosis there by reducing cognitive deficits. 39

42. ATTENTION-DEFICIT HYPERACTIVITY DISORDER ADHD is a disorder most prevalent in children characterized by persistent carelessness, hyperactivity, and impulsivity. In preclinical models, pharmacological alterations that antagonize the cholinergic system or enhance the various neurotrans- mitter systems like DA, orexin, cannabinoids systems including histamine cause hyperactivity [an increase in locomotor activity (LA)] that accompanies various neurological disorders including ADHD ). 40

43. Recently, H3R antagonist (carnicine, a stable analog of the naturally occurring dipeptide carnosine) attenuated hyperlocomotion in an ADHD-specific model with neonatal habenula lesion without having an effect on attention- deficit. 41

44. Schizophrenia Schizophrenia, a chronic debilitating neurological syndrome characterized by positive (e.g., hallucination and delusion), negative (e.g., paucity of emotion and motivation), and impaired cognitive symptoms. Dysregulation in DA and other neurotransmitter systems are involved in the development of the disease. Current pharmacotherapy for schizophrenia consists of first generation (FGA) and second generation (SGA) antipsychotics, which mainly act by DA antagonism in CNS mediated mainly by DA D2- receptors 42

45. But also by D3R and/or D4R, serotonin receptor (5-HTR) subtypes (5-HT2AR/5-HT2CR) and/or via modulation of the glutamatergic system which may evoke extrapyramidal (mainly FGAs) and/or serious metabolic disorders. H3R antagonist could be a pervasive therapeutic strategy owing to its pro-cognitive property. Histaminergic innervations into the brain areas closely associated with the development of schizophrenia raises the possibility of H3R antagonists influencing its pathophysiology. 43

46. H3R antagonists, enjoy the advantage of enhancing DA release from PFC(Prefrontal cortex). Thus may have a sparing effect on prefrontal function over strong DA antagonizing antipsychotics. H3R antagonist ciproxifan also reduced LA in methamphetamine induced chronic sensitization model. 44

47. ADDICTION Addiction is a complex condition, a brain disease that is manifested by compulsive substance use despite harmful consequence. One common mechanism for addiction caused by various drugs of abuse is thought to be the activation of brain’s reward circuitry. Circuitry pathway is connected to the ventral tagmental area (VTA) of the midbrain and their targets in limbic forebrain especially nucleus accumbens(NAc) where neurons release Dopamine  to make you feel pleasure. 45

48. However, other neurotransmitter systems including histamine are known to modulate the psychotropic effects of rewarding drugs. The fact that histamine also modulates mesolimbic DA transmission suggests that histaminergic drugs may be tried therapeutically in drug addiction. Nucleus accumbens (NAc) the main region involved in addiction, receive only weak his- taminergic innervations, very high densities of H 3 Rs which are present here. 46

49. Striatum contains one of the highest densities of H 3 Rs in the brain. Mainly, striatal H 3 Rs are located postsynaptically in the GABAergic efferent neurons where they are co-localized with D1 and D2 receptors. They are also located presynaptically on dopaminergic terminals in the striatum where they have an inhibitory role on DA release. 47

50. Histamine can also activate mesolimbic dopaminergic system possibly via presynaptic H 3 Rs located on DA terminals or postsynaptically on GABAergic neurons in striatum or through H1 Rs located on striatal cholinergic interneurons. Addictive drugs modulate the histamine levels in the brain. For instance, alcohol affects histamine levels in the brain by modulating histamine synthesis, release and turnover. 48

51. Acute injection of cocaine increases histamine levels and histamine-N-methyl transferase activity in the striatum and NAc and opioids (e.g., morphine) increases turnover of neuronal histamine via opioid receptors. On the other hand, histaminergic system can modulate behavioral effects of various drugs of abuse including cocaine, amphetamines, opioids, and alcohol. All addictive drugs stimulate LA (psychomotor stimulant effects). 49

52. Locomotion activation by amphetamine/methamphetamine and other dopaminergic agonists was attenuated by H3R block- ade by Thioperamide and Ciproxifan. 50

53. H 4 Antagonist H 4 receptor have been shown to play a role inflammatory conditions by virtue of their presence on the membrane of eosinophils and mast cells. Although no selective H 4 ligand is available. 51

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55. 3. Joseph George,  Mutsumi Tsuchishima &  Mikihiro Tsutsumi(08 Jan 2019). Molecular mechanisms in the pathogenesis of  N -nitrosodimethylamine induced hepatic fibrosis.   Nature Research (subsidiary of Springer Nature) 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895478/ 5. https://www.nature.com/articles/srep40541 6.https://www.sciencedirect.com/topics/psychology/histamine 53

56. 7.https://www.thehindu.com/news/national/drug-regulator-cautions-against-over-the-counter-use-of-ranitidine/article29511521.ece 8. Divya Vohora* and Malay Bhowmik (23 Oct 2012). Histamine H 3 receptor antagonists/inverse agonists on cognitive and motor processes :relevance to Alzheimer’s disease, ADHD, schizophrenia, and drug abuse. Frontiers in Systems Neuroscience. Volume 6|Article 72 | 1 . www.frontiersin.org 54

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