Science

Science

BioHealthonomics Inc. is a clinical stage biotechnology & healthcare company that will develop and commercialize both a product and a proprietary technology for the treatment and prevention of migraine headaches, Parkinson’s disease, Alzheimer’s disease, autism and other indications.

The National Headache Foundation estimates that US businesses lose $50 billion each year because of absenteeism, reduced employee productivity, and medical expenses caused by headaches. (JD Bartleson, Treatment of Migraine Headaches, Mayo Clin. Proc. 1999; 74; 702-708). It is the 10th most disabling disorder worldwide.

Parkinson’s disease is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. Despite extensive research in the area of PD, the precise pathogenesis remains largely unknown. Parkinson’s disease is characterized by motor and non-motor (cognitive and limbic) deficits. The economic burden of Parkinson’s disease is at least $14.4 billion a year in the United States, and the prevalence of Parkinson’s will more than double by the year 2040.

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimer’s, symptoms first appear after age 60. Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer’s disease.

With the first of the baby boomer generation now turning 65, the U.S. population aged 65 and over is expected to double by 2030. Although Alzheimer’s is not normal aging, age is the biggest risk factor for the disease. Taken together, these factors will result in more and more Americans living with Alzheimer’s – as many as 16 million by 2050, when there will be nearly one million new cases each year. Caring for people with Alzheimer’s will cost all payers – Medicare, Medicaid, individuals and private insurance — $20 trillion over the next 40 years. In 2012, the economic burden is estimated to be $200 billion in direct costs for those with Alzheimer’s.

It is estimated that total societal costs of caring for children with Autism Spectrum Disorder were over $9 billion in 2011. About 1 in 6 children in the United States had a developmental disability in 2006-2008, ranging from mild disabilities such as speech and language impairments to serious developmental disabilities, such as intellectual disabilities, cerebral palsy, and autism.

Histamine

Histamine is composed of an imidazole ring and an amino group connected by a short chain of two carbon atoms (Ganellin, 1982). It is a decarboxylation product of the amino acid histidine. It is the primary toxin released from basophils and tissue mast cells during an allergic reaction. There are four other causes of histamine release:

1) a reaction to certain drugs, peptides, venom, and other “liberators”;

2) a physical insult (thermal, vibratory, radiant, or exertional);

3) stress (chemical, traumatic, or osmotic); and

4) spontaneous basophil release, which is higher in atopic individuals (Clemis JD., 1995).

Histamine has a broad spectrum of activities in various physiological and pathological conditions including cell proliferation, differentiation hematopoiesis, embryonic development, regeneration, wound healing, aminergic neurotransmission and various brain functions (sleep, nociception, food intake and aggressive behaviour), secretion of pituitary hormones, regulation of gastrointestinal and cardiovascular systems.  It also regulates inflammatory reactions, modulation of the immune response, functioning of the endocrine system and homeostasis (Shahid et al. 2009).  An increase in histamine levels has been noticed in skin and plasma of patients with atopic dermatitis (AD), chronic urticaria (CU), multiple sclerosis (MS) and psoriatic skin (Thurmond et al. 2008).  An increase in histamine levels has been observed in plasma of patients with migraines.

It is well recognized that the fundamental pleiotropic regulatory character of histamine in cellular events is attributed to its binding to four subtypes of G-protein coupled receptors, designated H1, H2, H3 and H4 that are differentially expressed in various cell types.  Histamine’s physiologic actions are mediated by four types of cell receptors: H1, H2, H3 and H4. The principal receptors throughout the body are the H1 and H2 receptors. The H3 receptors help regulate the synthesis and release of histamine from central nervous system histaminergic nerve endings.

Histamine H1 Receptor

The histamine H1 receptor is a unique G-protein coupled receptor because the stimulation of the receptor induced and the receptor up-regulation through increase of gene expression.  Histamine-induced up-regulation of H1 receptor was mediated by protein kinase C-d signaling. Correlation between symptom and histamine H1 receptor mRNA level was observed, and the data strongly suggest that histamine H1 receptor gene is an allergic disease sensitive gene.  Drugs for allergy also showed strong suppression of IL-4 and IL-5 gene expression besides H1 receptor gene expression.

H1 distribution and occupancy in humans have also been mapped using functional imaging techniques to study the sedative properties and blood-brain barrier (BBB) permeability of H1R antihistamines, aging and neuropsychiatric disorders, such as Alzheimer’s disease, schizophrenia and depression, in all of which H1R binding was found lower than in the age matched healthy controls.  Histamine through H1R excites neurons in most brain regions, including brain stem, hypothalamus, thalamus, amygdala, septum, hippocampus and cortex.

Histamine H2 Receptor

The human H2R, which is a 40-kDa 359-amino acid peptide, is located on chromosome 5q35.5.  It has been documented that H2R is mostly involved in suppressive activities of histamine, while stimulatory effects are mediated through H1R.  The activation of H2R regulates various functions of histamine including heart contraction, gastric acid secretion, cell proliferation, differentiation and immune response. In the human brain, the highest densities of H2R are found in the basal ganglia, hippocampus, amygdale and cerebral cortex.  The lowest densities are found in the cerebellum and hypothalamus.  H2R stimulates accumulation of cyclic Adenosine Monophosphate (cAMP) (Hill et al. 1997, Soll and Walsh 1979) in a variety of tissue including gastric cells (Johnson 1982), cardiac tissue and brain (Al-Gadi and Hill 1985, 1987).  Hill (1990) had demonstrated that the effects of H2Rs can inhibit a variety of functions within the immune system.  H2Rs have been shown to negatively regulate the release of histamine in basophils and mast cells (Plaut and Lichtenstein 1982, Ting et al. 1980).  The inhibition of antibody synthesis, T-cell proliferation, cell mediated cytolysis, and cytokine production is further evidence of H2R presence on lymphocytes (Banu Watanabe 1999, Jutel et al. 2001, Melmon and Khan 1987).

Histamine H3 Receptor

The H3R was discovered in 1983 by the group of J.C. Schwartz in Paris.  Lovenberg et al. reported its cloning in 1999.  H3 receptors were described as presynaptic autoreceptors.  H3 receptors couple to Gi/o to inhibit adenylyl cyclase (Hough 2001, Leurs et al. 2001).  They mediate synthesis of histamine and inhibition of histamine release from histaminergic neurons.  The activation of H3 autoreceptors can inhibit histamine synthesis and also release while H3 receptor blockers can enhance the release of neurotransmitter (Fox et al. 2005, Medthurst  et al. 2007, 2009). Histaminergic dysregulation has been found in different CNS disorders.  Hence, H3 ligands are being investigated for their clinical utility particularly in Central Nervous System (CNS) disorders.  Many H3 receptor ligands are in early phase clinical trials for obesity, memory disorders, learning deficit and epilepsy (Parsons and Ganellin 2006).

Additionally, loss of H3R function is associated with behavioral state abnormalities, reduced locomotion, a metabolic syndrome with hyperphagia, late-onset obesity, increased insulin and leptin levels and an increased severity of neuroinflammatory diseases, in keeping with data from genetic linkage studies.  With its unique pharmacological properties, the H3R is a major target of drugs against various disorders of the brain.

Histamine H4 Receptor

The last of the four histamine receptors, H4 receptor (H4R), was identified in the year 2000. Since that time, H4R has been implicated in cellular mechanisms related to immune systems, inflammatory processes, and allergic reactions. H4 receptors are expressed in bone marrow, spleen, peripheral blood, small intestine, heart, colon, lung, etc. They are present in hematopoietic cells, neutrophils, mast cells, eosinophils, basophils, monocytes, T cells and dendritic cells (Leurs et al. 2009).  Many H4 receptors antagonists are in clinical phase trials for inflammatory conditions such as asthma and rheumatoid disease (Engelhardt et al. 2009, Jablonowski et al. 2003, Parsons and Ganellin 2006, Tiligada et al. 2009).

MIGRAINE: In 2003, Gazerani, et al. demonstrated a correlation between migraine, histamine, and immunoglobulin E.   Serum samples were collected (for histamine levels and Immunoglobulin E levels) from 70 patients (18 – 58 years) with migraine during an attack and during remission and from 45 healthy volunteers. The migraine patients were divided into two groups according to their history of allergies (60% having a history of allergies and 40% without a history of allergies).  Plasma histamine levels were significantly elevated (P ≤ 0.0001) in patients with migraine both during symptom-free periods and during migraine events when compared to the control group.

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From Gazerani et al., 2003

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From Gazerani et al., 2003

In 1991, Guerrero, et al. carried out an initial study that provided evidence for the beneficial effects of histamine in migraine prophylaxis (Millan-Guerrero RO, 1999). Their data showed that subcutaneous administration of low doses of histamine induced significant relief from migraine symptoms, with no secondary effects. The possible mechanisms of histamine-migraine prophylaxis can be explained by histamine control of mast cells; the antidromic stimulation of trigeminal nerve endings induces the release of substance P and other neuromodulatory peptides, which in turn stimulate the release of histamine from mast cells. In meningeal blood vessels, activation of H1-receptors by histamine, results in vasodilatation and plasma protein extravasation, causing neurogenic inflammation (Akerman S, 2002).  Krabbe and Olesen (Krabbe AA, 1980) and Lassen et al. (Lassen LH, 1995) showed that on migrainous subjects, intravenous administration of relatively high doses of histamine (0.5 mg/kg per minute for 20 min) caused an immediate headache during the infusion, followed by a delayed migraine attack which was abolished by pre-treatment with the H1-R antagonist, mepyramine. However, degranulation of mast cells and neuropeptide release from C fiber endings are inhibited by the histamine at low-concentration interaction with H3-receptors (H3-R), and probably reflects a local feedback circuit between C-fiber nerve endings and mast cells, which control neurogenic inflammation (Dimitriadou V, 1994) (Arrang J-M, 1983) (Arrang J-M G. M.-C., 1987)

PARKINSON’S DISEASE (PD): Histamine is involved in neuronal degeneration (Langlais et al 1994) and neurotoxicity (Thoburn et al 1994). Changes in the morphology and increase in density of histaminergic fibers in the substantia nigra have been described in the brain of PD patients (Anitchtchik et al 2001). It has been shown that histamine causes selective damage in the dopaminergic neurons of the substantia nigra with induction of inflammatory signal processes (Vizuete et al 2000). Histamine through H1R excites neurons in most brain regions, including brain stem, hypothalamus, thalamus, amygdala, septum, hippocampus and cortex. Among patients with PD, blood histamine levels (Coelho et al 1991) and the concentration of the histamine metabolite pros-methylimidazoleatic acid in the cerebrospinal fluid are increased (Prell & Green 1991). Taken together, these findings suggest that modulation of brain histamine may be related to PD, but the mechanisms underlying such modulation remains unknown.

Changes in the density and expression of histamine receptors (HR) have been detected in PD patients (Anichtchik et al 2001). HR antagonists bring about improvements in motor and other symptoms (Molinari et al 1995, Gomez-Ramirez et al 2006), thus suggesting that HRs play a role in the clinical response of PD patients.

Three types of histamine receptor, H1R through H3R are present in the human brain. H1R and H2R have been localized to caudate and putamen, and H3R is most abundant in the basal ganglia, the highest density being observed in the globus pallidus (Martinez-Mir et al 1990). The predominant location of HRH2 and HRH3 in the basal ganglia suggests that these receptors could play a role in motor functions (Martinez-Mir et al 1990).

Abnormally high histamine concentrations are found in the brains of PD patients (Nuutinen & Panula 2010). Rinne et al (2002) found histamine concentrations to be significantly increased in the putamen (to 159% of the control mean), substantia nigra pars compacta (SNc) (to 201%), internal globus pallidus (to 234%) and external globus pallidus (to 200%), i.e. in areas which play a crucial role in the motor behavior and which show typical functional alterations in PD. Concentrations of metabolite tele-methylhistamine were unchanged in PD, suggesting that histamine concentration, but not its metabolism is increased in PD.

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From Rinne and Panula 2002

Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and, as a consequence, exert important effects on motor control (Zhou F-W et al 2006).

ALZHEIMER’S DISEASE (AD): Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques accumulation and cognitive impairment. Both environmental factors and heritable predisposition have a role in AD. Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H4 receptor (H4R). The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy.

In Alzheimer’s disease (AD), several subcortical ascending projections, including the histaminergic neurons, display degeneration and tangle formation (Swaab DF, 1998). In the hypothalamus, neurofibrillary tangles occur exclusively in the tuberomamillary nucleus accompanied by reduced numbers of large neurons (Airaksinen MS, 1991; Nakamura S, 1993). Histamine and metabolite levels in the spinal fluid increase with increasing age (Prell, 1988), in contrast to other amines. A decline in histamine levels and/or HDC activity has been seen in Alzheimer’s disease (Ishunina T, 2003; Panula P, 1993) and Down’s syndrome (Kim SH, 2002; Schneider C, 1997;  Seidl R, 1997). Functional imaging studies show decreased brain H1R occupancy in Alzheimer’s disease compared with age-matched healthy controls (Yanai K, 1992), in keeping with cognitive impairments induced by the H1R antihistamine chlorpheniramine (Okamura N, 2000).

A sensitive high-performance liquid chromatographic fluorimetric method was used to measure histamine contents in post mortem Alzheimer brains and age-matched controls. The cellular storage sites and distribution of histaminergic nerve fibers were examined with a specific immunohistochemical method. The histamine content was significantly reduced in the hypothalamus (42% of control value), hippocampus (43%) and temporal cortex (53%) of Alzheimer brains. Differences in other cortical areas, putamen and substantia nigra were not significant. Histamine-containing nerve fibers were found in the hippocampus, parahippocampal gyrus and subiculum of both Alzheimer brains and controls. No histamine-containing mast cells were seen in these temporal structures.

Histamine in the human temporal lobe is stored in nerve fibers originating from the posterior hypothalamus, and not in mast cells. Decrease in brain histamine may contribute to the cognitive decline in Alzheimer’s disease directly or through the cholinergic system. Development of drugs that penetrate the blood-brain barrier and increase histaminergic activity might be beneficial in Alzheimer’s disease.