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  • Parkinson s disease is another neurodegenerative disorder

    2022-07-02

    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 DMXAA 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). The relationship between the attention deficit hyperactivity disorder (ADHD) and H3Rs is supported by several reports (Berlin et al., 2011; Passani, Bacciottini, Mannaioni, & Blandina, 2000; Vohora & Bhowmik, 2012). ADHD is a neurobehavioral disorder with high prevalence in children, with hyperactivity, inattention, impulsivity, agitation, and disorganized behavior as the most common symptoms. The exact mechanisms of ADHD are not clearly understood; however, it may arise from the dysfunction of noradrenergic and dopaminergic signaling. The most routinely used therapeutic agents for ADHD treatment are methylphenidate and atomoxetine as stimulant and non-stimulant agents, respectively. Although it seems that these agents increase norepinephrine and dopamine concentrations in neuronal synapses, there is evidence that histamine levels in the prefrontal cortex are also augmented. Since these drugs have significant adverse effects and great potential of being abused, H3R antagonists may represent a suitable alternative to the current therapeutics (Berlin et al., 2011; Passani et al., 2000). In addition, the neural histaminergic system is involved in schizophrenia. This disorder is originated by hyperactivity of the dopaminergic system, with psychotic symptoms such as hallucination, delusion, emotional pauperism, and lack of motivation (Sander et al., 2008; Vohora & Bhowmik, 2012). The currently used pharmacotherapy for schizophrenia focuses on antagonizing dopamine receptors, mainly D2 receptors, but extrapyramidal symptoms and metabolic actions (i.e. weight gain) are adverse effects associated with D2 receptor antagonists (Sadek, Saad, Sadeq, et al., 2016). Some studies show that Nτ-methylhistamine is enhanced in the cerebrospinal fluid of schizophrenic patients (Rapanelli & Pittenger, 2016; Sander et al., 2008), and abnormal H3R expression is observed in the brain of schizophrenic individuals (Rapanelli & Pittenger, 2016). In this context, compounds with inhibitory activity on H3Rs receptors can be promising agents to replace the pharmaceuticals in use. Besides, an additional benefit of H3R antagonists would be the induction of glutamate release, as glutamatergic hypoactivity is observed in this neuropsychiatric condition (Ellenbroek & Ghiabi, 2014).