Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology. Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy

Abstract

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO₂ nanowired BF 2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25 μL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.

Introduction

Parkinson's disease (PD) is one of the most prominent neurodegenerative movement disorders affecting mankind across the globe (Cuenca et al., 2019; Kalia and Lang, 2015; Samii et al., 2004; Tolosa et al., 2006). PD burden on mankind is associated with either due to environmental, toxicological or genetic defects (Axelsen and Woldbye, 2018; Balestrino and Schapira, 2020; Bellou et al., 2016; Jankovic and Tan, 2020; Hatcher et al., 2008; Kim and Alcalay, 2017; Lang and Espay, 2018). About 10 million people are suffering from PD World-wide out of which about 1.8 million are living in the United States (Collier et al., 2017; Tysnes and Storstein, 2017). Epidemiological data suggest that about 60 k people are diagnosed with PD every year with mortality rate of 23 k each year in the United States (Ascherio and Schwarzschild, 2016). In Europe the prevalence of PD are estimated at about 110–258 cases per 100 k populations (von Campenhausen et al., 2005). In terms of PD each year about 10–20 cases per 100 k populations are diagnosed in Europe (Canevelli et al., 2019).

The cardinal symptoms of PD include tremor, rigidity, bradykinesia or akinesia together with postural instability but several non-motor symptoms are also identifies in clinical cases (Armstrong and Okun, 2020; Balestrino and Schapira, 2020; Jankovic, 2008; Marino et al., 2020; Peball et al., 2020). The neuropathological symptoms of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpC) and striatum (STr) (Lopiano et al., 2019; Marino et al., 2020; Santos-García et al., 2020). In addition, the hallmark of PD includes accumulation of misfolded protein alpha synuclein (ASNC) and deposits of Lewy bodies (LBs) (Chatterjee et al., 2020; Guo et al., 2020; Kyle and Bronstein, 2020; Pennington et al., 2020; Shahnawaz et al., 2020; Sonninen et al., 2020). With advancement of time the neurodegenerative changes spread all over the brain leading to serious consequences and death. Treatment strategies for PD cases are so far symptomatic and largely focused on the dopaminergic pathways (Qian et al., 2020; Ruppert et al., 2020). However, no satisfactory treatment regimen so far has emerged. Thus, this is highly warranted to expand our knowledge on the PD pathophysiology in order to explore novel clinical therapy using nanomedicine.

PD is characterized by the progressive loss of dopaminergic neurons in the SNpC and STr leading to dopamine deficiency (Drew et al., 2020; Schweitzer et al., 2020; Yang et al., 2020). However, other neurotransmitters are also present in the brain affecting motor functions and related to PD pathology (Iarkov et al., 2020; De Deurwaerdère and Di Giovanni, 2020). Histamine is one of the key regulatory neurotransmitters that are widely distributed in the brain (Esbenshade et al., 2008; Provensi et al., 2020; Prell and Green, 1986; Schwartz et al., 1980). The cell bodies of approximately 64 k histaminergic neurons are located in the posterior hypothalamus of the tuberomamillary nucleus (TMN) and send its projections to almost all areas of the cerebral and cerebellar cortex in the brain (Giannoni et al., 2009; Khedkar et al., 2012; Moriwaki et al., 2015; Umehara et al., 2012). From TMN the exclusive site of neuronal histamine production SNpC receives dense histaminergic innervation (Anichtchik et al., 2000a, Anichtchik et al., 2000b; Maisonnette et al., 1998; Panula et al., 1989; Shan et al., 2012). Apart from dense histaminergic innervation in SNpC enlarged axonal varicosities and increased histamine levels were found in SNpC of PD patients (Rinne et al., 2002; Shan et al., 2012, Shan et al., 2013, Shan et al., 2015). Evidences suggest that increased endogenous histamine levels induce degeneration of dopaminergic neurons in PD (Anichtchik et al., 2001; Liu et al., 2007). The blood levels of histamine and histamine metabolite in the cerebrospinal fluid (CSF) are increased in PD (Anichtchik et al., 2000a, Anichtchik et al., 2000b; Kempuraj et al., 2016; Prell and Green, 1986). In addition, blockade of histamine H2 receptors in PD reduces bradyphrenia and improve motor functions in some patients of PD (Molinari et al., 1995). Histaminergic innervation also increased in the areas of dopaminergic innervation in SNpC and STr in PD (Auvinen and Panula, 1988; Panula et al., 1989, Panula et al., 1990).

Histamine has several receptors in the brain and central nervous system that regulate or modulate several functions and effects of other neurotransmitters in health and disease (Annamalai et al., 2020; del Rio et al., 2012; Moreno-Delgado et al., 2020; Parsons and Ganellin, 2006; Panula et al., 2015; Tiligada et al., 2011).

Recent studies demonstrate that drug targeting of histamine H3 and H4 receptors could be beneficial in a large number of neurological diseases (del Rio et al., 2012; Naddafi and Mirshafiey, 2013; Patnaik et al., 2018; Saligrama et al., 2012; Teuscher et al., 2007). Histamine H3 and H4 receptors are altered in the brain of PD patients (Shan et al., 2012). Thus, a possibility exists that Histamine H3 and H4 receptors could modulate brain pathology in PD (Chen et al., 2020; Koski et al., 2020,b; Nuutinen and Panula 2010; Panula and Nuutinen, 2013). It would be interesting to compare nanodelivery of select histamine H3 and H4 receptor modulator drugs with nanowired delivery in PD to induce superior neuroprotective effects (Patnaik et al., 2000, Patnaik et al., 2018; Sharma et al., 2017a, Sharma et al., 2017b, Sharma et al., 2019a, Sharma et al., 2019b). Histamine appears to be involved in the pathophysiology of PD. Thus, it would be interesting to see whether administration of histamine antibodies could exert additional beneficial effects in PD together with histamine H3 or H4 receptor modulator agents in inducing superior neuroprotection (Sharma and Cervós-Navarro, 1991; Sharma et al., 1992a, Sharma et al., 1992b, Sharma et al., 2006a, Sharma et al., 2006b, Sharma et al., 2016a, Sharma et al., 2016b, Sharma et al., 2016c, Sharma et al., 2017a, Sharma et al., 2017b).

In this chapter we used nanowired delivery of histamine H3 and H4 rector modulator agents together with histamine antibodies to explore potential therapeutic roles of histaminergic neurotransmission in PD based on our own investigations. The functional significance of our findings in the light of current histamine research is discussed.

Histamine [2-(1H-imidazol-4-yl)ethanamine] is a biogenic amine distributed ubiquitously throughout the brain and several tissues in the body (Haas et al., 2008; Yoshikawa et al., 2019). Histamine was first discovered by Sir Henry Dale in 1910 in mammalian tissues that dilates blood vessels and contracts smooth muscles and could be involved in anaphylaxis reaction (Dale and Laidlaw, 1910). Histamine is synthesized by amino acid l-histidine by catalytic activity of histidine decarboxylase (HDC) (Holeček, 2020; Moriguchi and Takai, 2020; Watanabe and Ohtsu, 2002). Histamine is catabolized by the cytosolic enzyme histamine N-methyltransferase to N-methylhistamine or by extracellular enzyme diamine oxidase to imidazole acidic acid (Kitanaka et al., 2016; Shan et al., 2017; Weinshilboum et al., 1999).

Histamine in the brain largely in the gray matter was for the first time described by Kwiatkowski (1941) and White demonstrated its formation and catabolism in the brain in 1959 (White, 1959, White, 1961). In 1974 histaminergic projections in the brain was shown by Garbarg using lesion of the median forebrain bundle (Garbarg et al., 1974). However, fluorescent immunohistochemical demonstration of histaminergic neurons in brain was first identified in 1983 by Watanabe in Osaka, Japan (Watanabe et al., 1983) and later immunohistochemical distribution of histaminergic nerve cells and fibers was shown in all most all parts of the brain extensively in 1984 by Panula in Washington DC, USA (Panula et al., 1984). Later, Panula, Steinbusch and others from 1988 to 1998 showed extensive details of histaminergic neurons and its projections throughout the rat brain and spinal cord and in human brain (Smits et al., 1990; Steinbusch 1991; Steinbusch et al., 1986; Wouterlood et al., 1986, Wouterlood et al., 1987, Wouterlood et al., 1988). These immunocytochemical mapping of histaminergic neurons established its role as a neurotransmitter in the central nervous system (CNS) (Brandes et al., 1990; Haas et al., 2008; Schwartz et al., 1980).

With recent advancements in drugs targeting histamine receptors for various diseases, four metabotropic receptor types are identified as histamine H1, H2, H3 and H4 (Chazot, 2013; Panula et al., 2015; Roeder, 2003; Tiligada and Ennis, 2020). The histamine H1, H2 and H3 are expressed in abundance in the brain whereas histamine H4 receptors are largely found in peripheral tissues but recently their functional expression in brain is also described (Connelly et al., 2009; Fang et al., 2021; Martinez-Mir et al., 1990; Parsons and Ganellin, 2006; Schneider et al., 2015; Zhou et al., 2006). Drugs targeting H4 receptors in brain showed Histamine H4 receptors were prominently expressed in neurons of human cerebral cortex in layer VI (Feliszek et al., 2015). In mouse histamine H4 expression is seen in nerve cells located in the thalamus, hippocampal CA4, stratum lucidum and cerebral cortex layer IV (Feliszek et al., 2015. Based on these studies several histamine H3 agonists and H4 antagonists are developed that are used to target CNS disorders (Nieto-Alamilla et al., 2016; Patnaik et al., 2018; Sharma et al., 2017a, Sharma et al., 2017b; Zhou et al., 2019. All metabotropic histamine receptors belong to class A rhodopsin like family of G-protein coupled receptors (GPCRs) (Conrad et al., 2020; Hishinuma et al., 2016; Strasser et al., 2013). The histamine H1 and H2 receptors have low-affinity for histamine as compared to histamine H3 and H4 receptors that are high affinity histamine receptors (Čarman-Kržan and Lipnik-Štangelj, 2000; Fossati et al., 2001.

Histamine in the brain is implicated in a variety of normal brain functions as well as in several disease processes leading to neurodegeneration (Barata-Antunes et al., 2017). These effects are mediated through various histamine receptors (McClain et al., 2020).

Behavioral studies indicate role of histaminergic system in cognitive functions through histamine H1, H2 and H3 receptors (Santangelo et al., 2017). Thus is further supported by high degree of expression of these receptors in brain regions including cerebral cortex, thalamus, hypothalamus, hippocampus and amygdala involved in cognition (Alvarez, 2009). Intracerebroventricular (i.c.v.) administration of histamine facilitates step-down inhibitory avoidance behavior that is mediated through histamine H1 and H2 receptors (Mayer et al., 2018). Furthermore mice lacking histamine H1 and H2 receptors exhibited impaired object recognition and acquisition of spatial memory (Dai et al., 2007; da Silveira et al., 2013; Passani et al., 2017).

Pharmacological data suggests that histamine H3 receptor antagonists improve cognitive functions in animal models and alleviates cognitive deficits in transgenic amyloid precursor protein (APP) mutant mouse model of Alzheimer's disease (AD) (Brioni et al., 2011; Medhurst et al., 2009; Witkin and Nelson 2004). In human cases of AD histamine levels are decreased in the hippocampus, temporal cerebral cortex and hypothalamus (Cacabelos et al., 1989; Jaarsma et al., 1994). This suggests that histaminergic neurons degeneration is likely to contribute cognitive decline in AD. Several histamine H3 receptor antagonists are being tried in clinical trials Phase I and II to improve cognitive functions in AD, schizophrenia and attention-deficit hyperactivity disorder (ADHD) (Ellenbroek and Ghiabi, 2015; Kubo et al., 2015; Minzenberg and Carter, 2008; Rapanelli and Pittenger, 2016; Sadek et al., 2016; Weisler et al., 2012). However, the results are still inconclusive.

Increased levels of histamine are found in the substantia nigra, putamen and globus pallidus in Parkinson's disease patients (Rinne et al., 2002). Postmortem finding show a decrease in TMN neurons in patients of multiple brain atrophy, but not seen in PD cases (Shan et al., 2012; Yamada et al., 2020). In animal models of PD induced with 6-hydroxydopamine (6-OHDA) lesioned animals histamine levels are increased in the brain similar to human cases in PD (Nowak et al., 2009). This suggests that increased histamine in brain is associated with PD associated with insomnia. Interestingly histamine H3 and H4 receptor antagonist reduces apomorphine-induced stereotyped behavior in 6-OHDA lesioned animals (Farzin and Attarzadeh, 2000; Liu et al., 2008).

As mentioned above histamine H1, H2 and H3 receptors are expressed in high densities within the brain areas in the cerebral cortex, hippocampus, dorsal thalamus (Arrang, 2007; Ellenbroek and Ghiabi, 2015; Iwabuchi et al., 2005). These brain regions are involved in cognitive functions and are severely disrupted in schizophrenia (Besteher et al., 2020; Guo et al., 2019). In addition, brains of schizophrenic patients histaminergic system are severely perturbed. Increased levels of histamine metabolite tele-methylhistamine reflecting histamine release are found in the CSF of schizophrenic patients (Brioni et al., 2011; Nakai et al., 1991). The histamine H1 receptor binding is reduced in prefrontal, frontal and cingulate cortices in brains of patients with schizophrenia (Ito 2004; Mahmood et al., 2012; Orange et al., 1996). On the other hand, histamine H3 receptor biding is increased in dorsolateral prefrontal cortex in schizophrenic patients. Treatment with histamine H3 receptor antagonist induced beneficial therapeutic effects in schizophrenia patients (Brioni et al., 2011; Browman et al., 2004; Mahmood et al., 2012).

The autoimmune disease multiple sclerosis (MS) is associated with demyelination, neuroinflammation, axonal degeneration and neuronal loss (Absinta et al., 2020; Filippi et al., 2020; Hauser and Cree, 2020). In animals models experimental autoimmune encephalomyelitis (EAE) clearly indicated involvement of histamine in the pathological processes (Jadidi-Niaragh and Mirshafiey, 2010; Rafiee Zadeh et al., 2018). In remitting or progressive patients of MS histamine levels in the CSF are more than 60% higher than healthy cases (Kallweit et al., 2013; Tuomisto et al., 1983). Also the histamine H1 receptor mRNA is upregulated in MS lesions (Lu et al., 2010). Treatment with histamine H1 receptor antagonist improves neurological benefits in MS patients and the onset of the disease (Alonso et al., 2006; Logothetis et al., 2005).

Involvement of histamine is amply shown in human cases and in animal models in sleep dysfunction (Diez-Garcia and Garzon, 2017; Scammell et al., 2019; Thakkar, 2011). Available data show that histamine levels are decreased in the cerebrospinal fluid (CSF) in humans with idiopathic hypersomnia or narcolepsy (Dauvilliers et al., 2013; Szakacs et al., 2017). This suggests that histamine is involved in alertness and wakefulness. Treatment with histamine H2 receptor antagonists improves sleep quality in narcolepsy patients (Thorpy, 2020). Based on these data it appears that low histamine levels in brain or CSF is related with increased sleepiness (Bassetti et al., 2010; Franco et al., 2019; Kanbayashi et al., 2009; Nishino et al., 2009).

Studies showing lesion of TMN neurons or treatment with histamine H1 receptor antagonist induces an inhibitory effect on reward and reinforcement as well as addictive behavior (Brabant et al., 2010; Halpert et al., 2002; Pallardo-Fernández et al., 2020). Histamine H3 receptor antagonists potentiate self-administration of morphine or alcohol (Mobarakeh et al., 2009; Owen et al., 1994; Panula, 2020; Panula and Nuutinen, 2011; Popiolek-Barczyk et al., 2018; Vanhanen et al., 2013). This treatment also reinforces methamphetamine or cocaine preference (Kitanaka et al., 2011; Okuda et al., 2009; Munzar et al., 2004; Moreno et al., 2014; Pallardo-Fernández et al., 2020). This potentiation of methamphetamine and cocaine are also modulated by histamine H3 and H4 receptors (Corrêa and dos Santos Fernandes, 2015; Schneider et al., 2014; Sharma and Ali, 2006, Sharma and Ali, 2008; Sharma et al., 2014, Sharma et al., 2009a, Sharma et al., 2009b; Thurmond, 2015). Experiments in our laboratory show that morphine dependence and withdrawal symptoms are lessened in rats with histamine H3 and H4 receptor modulation (Sharma HS unpublished observation).