Fig illustrates the different signaling pathways

Fig. 1 illustrates the different signaling pathways elicited or modulated by H3R activation. Collectively, the modulation of the release of histamine and other neurotransmitters through H3R activation could be linked to several neurological disorders such as sleep disorders like narcolepsy, Alzheimer's disease, attention deficit and hyperactivity disorder (ADHD), Parkinson's disease, schizophrenia, multiple sclerosis, Tourette's syndrome, pain, obesity etc (Bhowmik et al., 2012; Brioni, Esbenshade, Garrison, Bitner, & Cowart, 2011; Gemkow et al., 2009; Lin, Sergeeva, & Haas, 2011; Passani et al., 2017; Passani & Blandina, 2011; Provensi, Blandina, & Passani, 2016; Shan, Bao, & Swaab, 2015). Fig. 2 shows the clinical trials reported for H3R antagonists/inverse agonists in relation to neurological disorders and other diseases.
Histamine has an important role in the light/dark cycle in which histamine levels increase during wakefulness to decline to the baseline level during sleep (Brioni et al., 2011; Lin et al., 2011; Meredith & Tony, 2011). Therefore, enhanced histamine neurotransmission due to H3R blockade improves wakefulness and vigilance in individuals suffering from narcolepsy during daytime (Gondard et al., 2013). Narcolepsy is defined as uncontrollable excessive sleepiness and irregular onset of rapid eye movement (REM) sleep during the daytime that affect the quality of life. Episodes of sudden loss of muscle control (known as cataplexy) are experienced by most narcoleptic individuals (Calik, 2017). The wake promoting effect of H3R antagonists has been well documented and several studies have shown that antagonizing H3R receptors results in increased histamine levels, which in turn augment the activation of post-synaptic H1 receptors leading to enhanced wakefulness (Broderick & Masri, 2011; Gondard et al., 2013; Lin et al., 2011; Parmentier et al., 2007; Thakkar, 2011). The advantage of H3R antagonists over classical psychostimulants is the lack of locomotor activity, behavioral excitation, and sleep rebound (Berlin et al., 2011; Broderick & Masri, 2011; Lin et al., 2011). Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder with cognitive deficit and memory impairment in the geriatric population. Although the cholinergic system is mainly targeted for enhancing KB SRC 4 levels by inhibiting its enzymatic degradation, the role of H3Rs in modulating acetylcholine release should not be neglected. Nonetheless, the role of the histaminergic system in the pathophysiology of AD is not completely understood and some discrepancies still exist. For example, some reports indicate hyperactivity of the CNS histaminergic system, whereas other studies reveal a loss of histaminergic neurons in AD (Shan et al., 2015; Vohora & Bhowmik, 2012). However, recent reports are indicative of H3R-mediated regulation of acetylcholine release leading to elevated levels in cortex and hippocampus (Brioni et al., 2011; Esbenshade et al., 2008; Sadek, Saad, Sadeq, Jalal, & Stark, 2016). On the other hand, H3R antagonism increases CREB and GSK3β phosphorylation resulting in improvement of cognitive processes (Brioni et al., 2011; Leurs et al., 2005; Sadek, Saad, Sadeq, et al., 2016; Sander, Kottke, & Stark, 2008). Parkinson's disease is another neurodegenerative disorder affecting H3Rs. The most common clinical symptoms of this disease are rigidity, bradykinesia, rest tremor, loss of postural reflexes, and gain impairment owing to progressive degeneration of the dopaminergic neurons in the nigro-striatal neuronal pathway (Ellenbroek & Ghiabi, 2014; Shan et al., 2015). As a result, the excitatory and inhibitory activity of dopamine D1 and D2 receptors, respectively, in the striatal GABAergic projection neurons is attenuated, leading to enhanced activity of GABAergic nigro-thalamic neurons, which in turn inhibit the activity of cortical neurons (Ellenbroek & Ghiabi, 2014; Nieto-Alamilla et al., 2016). The current pharmacotherapy of parkinsonian patients focuses is based on the strategy to replace, to prolong or to imitate the activity of endogenous dopamine. However, the main adverse effect associated with chronic administration of such therapeutics is tardive dyskinesia arising from excessive D1 receptor-mediated signaling in the basal ganglia and enhanced cortico-striatal glutamatergic transmission (Ellenbroek & Ghiabi, 2014; Nieto-Alamilla et al., 2016). There are several reports indicating the involvement of H3Rs in modulating striatal GABAergic, glutamatergic, and dopaminergic transmission, mainly by inhibiting the release of GABA, glutamate, and dopamine (Arias-Montaño, 2008; Garcia, Floran, Arias-Montano, Young, & Aceves, 1997; Nieto-Alamilla et al., 2016). Furthermore, studies have shown that the increased levels of histamine in substantia nigra (SN) contribute to the degeneration of dopaminergic neurons. Besides, higher expression of H3Rs in substantia nigra pars reticulata (SNr) may contribute to the pathophysiology of Parkinson's disease (Arias-Montaño, 2008). In this respect, H3R antagonists can be promising therapeutic agents in Parkinson's disease through the stimulation of GABA and dopamine release in the SNr and striatum, respectively. In addition, H3R agonists can reduce dyskinesias induced by excessive dopamine D1 receptor signaling (Ellenbroek & Ghiabi, 2014; Nieto-Alamilla et al., 2016).