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Review

Pathophysiology of Alzheimer’s Disease: Focus on H3 Receptor Modulators and Their Implications

by
Nagaraju Bandaru
1,
Sarad Pawar Naik Bukke
2,
Veera Mani Deepika Pedapati
3,
Gurugubelli Sowjanaya
3,
Vangmai Swaroopa Suggu
3,
Swathi Nalla
4,
Prashik Bhimrao Dudhe
1,
Joseph Obiezu Chukwujekw Ezeonwumelu
5,
Abdullateef Isiaka Alagbonsi
6 and
Hope Onohuean
7,8,*
1
School of Pharmaceutical Sciences (SOPS), Sandip University, Nasik 422213, India
2
Department of Pharmaceutics and Pharmaceutical Technology, Kampala International University, Western Campus, Ishaka-Bushenyi P.O. Box 20000, Uganda
3
Department of Pharmacy Practice, Aditya Pharmacy College, Surampalem, Kakinada 533437, India
4
Department of Pharmacology, Malla Reddy Pharmacy College, Maisammaguda, Hyderabad 500014, India
5
Department of Clinical Pharmacy and Pharmacy Practice, Kampala International University, Western Campus, Ishaka-Bushenyi P.O. Box 20000, Uganda
6
Department of Physiology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Butare, Rwanda
7
Metagenomics, Endocrine, and Tropical Disease Research Group (BMETDREG), Kampala International University, Western Campus, Ishaka-Bushenyi P.O. Box 20000, Uganda
8
Biopharmaceutics Unit, Department of Pharmacology and Toxicology, School of Pharmacy, Kampala International University, Western Campus, Ishaka-Bushenyi P.O. Box 20000, Uganda
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2025, 4(2), 22; https://doi.org/10.3390/ddc4020022
Submission received: 28 March 2025 / Revised: 30 April 2025 / Accepted: 9 May 2025 / Published: 16 May 2025
Browse Figures
Versions Notes

Abstract

:
Current treatment options for Alzheimer’s disease target neurotransmitters following the disease onset, and they offer limited efficacy without slowing down the disease progression. There has been an increasing concern in recent years targeting the histamine H3 receptor (H3R) in treating cognitive disorders, including dementia. Preclinical studies have shown that antagonists of H3R or inverse agonists enhance the cognitive function in animal models with dementia by increasing the release of neurotransmitters associated with learning and memory. This review employed a systematic literature search across databases including PubMed, Scopus, Google Scholar, and ClinicalTrials.gov, selecting peer-reviewed studies. The results of this study illustrate the complex landscape of research on H3R modulators in dementia, highlighting both promising findings and ongoing challenges in translating preclinical discoveries into effective clinical interventions. Knowing the role of H3R in dementia and developing novel pharmacological interventions targeting these receptors represent a promising avenue for future research, leading to the development of new treatments for this devastating condition.

Graphical Abstract

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative and incapacitating condition marked by the gradual deterioration of cognitive abilities, specifically the impairment of memory and diminished reasoning. This is the primary cause of cognitive decline in elderly individuals, affecting many people globally. The disease, named after the German neurologist Alois Alzheimer, who initially documented the condition in 1906 [1], primarily impacts the brain by causing the buildup of atypical protein deposits like beta-amyloid plaques and tau tangles, and the death of nerve cells. These atypical formations interfere with the regular transmission of signals between neurons, leading to the progressive decline of cognitive functions like memory, language, problem-solving, and daily activities [2].
The precise etiology of AD remains elusive; however, advancing age, genetic predisposition, and lifestyle factors are considered potential determinants in its pathogenesis. The disease exhibits individual variability in its progression, typically commencing with mild symptoms that gradually deteriorate over time [2]. AD not only impacts the individuals who are diagnosed but also imposes considerable emotional and psychological strains on their families and caregivers.
Despite thorough investigations, there is presently no remedy for AD as the available treatment options only mitigate symptoms to improve the quality of life of the patients. Thus, current scientific endeavors are concentrated on comprehending the fundamental mechanisms of the disease, creating early diagnostic assays, and investigating potential therapeutic interventions.

2. Drug Targets for the Treatment of AD

Ongoing research into drug targets for AD is advancing, with an exploration of the multiple potential targets. It is crucial to acknowledge that drug development is an intricate procedure, and numerous potential treatments undergo a thorough examination in preclinical and clinical trials before being released in the market. Scientists are constantly investigating new methods, and our knowledge of the underlying causes of AD is developing. The primary drug targets that are being studied for AD are summarized below.

3. Beta-Amyloid Plaque and Its Role in AD

Beta-amyloid (Aβ) is a protein that creates deposits in the brain of people with AD. Scientists have been investigating medications that specifically target Aβ to decrease its production or improve its removal. Nevertheless, clinical trials focused on Aβ have yielded inconclusive outcomes, thus, its importance in this disease continues to be actively studied.
The posttranslational modification of amyloid precursor protein (APP) involves cleavage at α- or β-side enzymes, and the processing of the C-terminal fragment produced by gamma secretase. If the cleavage is from the α-secretase product, it results in a non-toxic protein fragment (p3), but the products of the cleavages by the Beta site cleavage enzyme (BACE) and the Gamma secretase yield 38-43 amino acid fibrillogenic Aβ, though Aβ42 is very prone to deposition in the core neurotic plaques [3]. To reduce Aβ production, efforts have been made to target drugs that can activate alpha secretase [4,5] or inhibit beta and gamma secretase [6,7,8]. The degradation of the toxic form of Aβ is also a target for dementia management, as Aβ degradation enzymes are low in human [9] and animal [10] models of AD, and the endogenous pathways to achieve this include neutral endopeptidase (neprilysin) [11,12], metalloproteinase, endothelin-converting enzyme, and angiotensin-converting enzyme.
Studies have shown that the constitutive monomer form of Aβ or the fibrillar network form aggregated in plaques is not the synaptotoxic form [13,14], but rather the oligomerization of monomeric Aβ into dimer, trimer, and other higher molecular mass combinations at the aggregation stage. Thus, oligomeric inhibition is a top target for the prevention of AD. Some agents that are at different stages of clinical trial for the prevention of the oligomerization of the Aβ monomer include grape-derived polyphenols [15], curcumin, and Omega-3 fatty acids [16].

4. Involvement of Tau Protein in AD

Intracellular neurofibrillary tangle, which is a condensed form of the cytoskeletal structure consisting of hyperphosphorylated helical paired filaments of microtubules associated with Tau protein, is the second pathological marker of AD. While Tau phosphorylation is important for its functioning, the hyperphosphorylated Tau no longer binds the microtubule but rather aggregates into paired helical filaments [17], ultimately leading to microtubule instability and disruption of axonal transport. Various kinases, including glycogen synthase kinase 3 beta (GSK-3β) and cyclin-dependent kinase 5, which are involved in tau hyperphosphorylation, have been identified and are also therapeutic targets. Agents like lithium and valproate inhibit GSK-3β to stabilize tau. Protein phosphatases, which dephosphorylate tau, are also an important target for the inhibition of hyperphosphorylation [18,19].

5. Cholinergic System and Its Effects in AD

The inhibition of cholinergic function leads to attention deficit, while the facilitation of cholinergic transmission improves it [20,21]. The major role of the cholinergic system in the learning process [22] and memory [23] has been established, as endogenous acetylcholine modulates the acquisition [24], encoding [25], consolidation [26], reconsolidation [27], extinction [28], and retrieval of memory [29]. In fact, memory loss in AD patients is associated with cholinergic neuron degeneration from the nucleus basalis of Meynert [30,31,32]. There is evidence showing that cholinergic system disruption impairs memory, attention, and learning [33,34]. Some examples of drugs that target the cholinergic system are acetylcholinesterase (AChE) inhibitors and neuronal nicotinic receptors’ agonists [35,36,37].

6. Serotonergic Pathway Modulation in AD

The expression of serotonin receptors in the brain areas important for memory and learning, and their decline in AD and dementia, have been well-established [38,39]. Moreover, the beneficial effect of selective agonists and antagonists of serotonin receptors on cognition in animal [40] and human [41,42] models has been reported.

7. Inflammation and Its Effects in AD

Neuroinflammation is thought to contribute to the advancement of AD. Researchers are currently studying the anti-inflammatory medications and substances that specifically target inflammatory pathways as potential treatments for AD. Some drugs involved in the regulation of inflammation that are under different clinical trial phases for AD are Masitinib [43,44], NE3107 [45,46], Semaglutide [47], AL002 [48], Bacillus Calmette-Guerin [49], Baricitinib [50,51], Canakinumab [52], Daratumumab [53,54,55], Lenalidomide [56], Montelukast [57,58], Pepinemab [59], Proleukin [60,61], Rapamycin [62,63], Sargramostim [64,65], Senicapoc [66], TB006 [67], the Tdap vaccine [68,69], Valacyclovir [70], XPro1595 [71], CpG1018 [72], Emtricitabine [73], IBC-Ab002 [74,75], Salsalate [76,77], and VT301 [78].

8. Neuroprotective Factors as Regulators of AD

Certain studies focus on investigating factors that enhance the resilience of nerve cells, shielding them from harm and boosting their longevity. This encompasses neurotrophic factors and other molecules that have the potential to augment neuronal resilience, enhancing synaptic plasticity, or producing neuroprotective effects. Some of the drugs at different phases of clinical trial for neuroprotective effects in AD include AGB101 [79,80], Blarcamesine [81], Fosgonimeton [82,83,84], Simufilam [85,86,87], Tertomotide [88,89], AL001 [90,91,92], Bryostatin1 [93,94], CY6463 [95], Dalzanemdor [96], Edonerpic [97], Elayta [98], EX039 [99], ExPlas [100], MW150 [101], Neflamapimod [102,103], and Centella asiatica [104].

9. Neurogenesis in AD

Agents that promote neurogenesis are among those that are in the pipeline for the treatment of AD. An example is allopregnanolone, an allosteric modulator of inhibitory gamma-aminobutyric acid-A receptors, which reduces the deposition of Aβ and enhances memory and learning [105]. Another example is sovateltide, an Endothelin-B receptor antagonist that promotes the differentiation of neuronal progenitors for the production of mature neuronal cells. This agent exhibits anti-apoptotic and antioxidant properties while also enhancing mitochondrial functions [106].

10. Role of the Genetic Factor in AD

Persons carrying apolipoprotein E Ɛ 4 are at high risk of developing AD at an earlier age, as it leads to increased Aβ deposition in the brain by regulating the passage of Aβ from the blood to the brain. Some drugs target the apolipoprotein E Ɛ 4 gene carrier (APOE4), being a very influential risk factor after the age of an individual and the most vital genetic factor for the development of AD. This protein has a strong interaction with Aβ, thereby reducing the amyloid brain accumulation age and elevating the total Aβ burden in gene carriers [107]. Furthermore, APOE4 exacerbates Tau neurofibrillary tangle-related blood–brain barrier disruption, neurodegeneration, microglial responses, astroglial activity, and neuroinflammation [108]. Some therapies targeting this marker are hydroxypropyl-beta-cyclodextrin [109], LX 1001, and obicetrapib [110].

11. Oxidative Stress and Its Role in AD

Shreds of evidence have shown that the enhancement of antioxidant status and attenuation of oxidative stress can reduce, prevent, or treat AD, as the foods rich in polyphenols, antioxidants, and polyunsaturated fatty acids reduce AD risk [111]. Drugs like hydralazine [112] and edaravone [113], among others, are at various clinical trial stages for the management of AD.

12. Others

Other mediators and pathways are targeted for drug development in the management of AD. Some of these are drugs that regulate vascular factors (telmisartan, perindopril), circadian rhythm (piromelatine) [114], and epigenetics (lamivudine) [115].

13. Lifestyle and Supportive Interventions

Non-pharmacological interventions are essential for effectively managing the symptoms of AD. These factors encompass cognitive stimulation, physical activity, and a nutritious diet. Establishing a nurturing and organized setting can additionally improve the general welfare of individuals with AD.

14. Clinical Trials and Research on Histamine Receptors in AD Treatment

Ongoing research is being conducted to formulate novel treatments and therapies for AD. Clinical trials provide the opportunity to access experimental medications or interventions that are currently undergoing testing to determine their efficacy. The AD research is constantly evolving, with continuous endeavors to discover novel therapeutic targets and create more efficient interventions. It is recommended that individuals suffering from AD, their families, and their caregivers remain updated on the most recent research discoveries and treatment choices by consulting with healthcare professionals and reliable sources.

15. Histamine

Histamine is a neurotransmitter that performs various physiological functions in the body through four receptor subunits, including the G-protein coupled H1R, H2R, H3R, and H4R. Various agonists and antagonists were developed for these receptors [116]. Allergic indications like asthma, rhinitis, conjunctivitis, and atopic dermatitis are treated with H1R antagonists [117]. The activation of H2R stimulates the gastric secretion while H1R and H2R mediate the opposing pharmacological and physiological effects on lungs and heart [118]. H3R is a presynaptic autoreceptor that inhibits the production and release of histamine in histaminergic neurons [119], while H4R is expressed in the immune cells. Evidence has shown that both H3R and H4R have homology, and some H3R agonists and antagonists equally bind to H4R [120]. A recent nationwide cohort study in Taiwan showed that the use of H1R antagonists is linked with increased dementia risk [121].
H3R is encoded on chromosome 20 and is displayed in many regions of the brain, like the cerebral cortex, CNS basal ganglia, and hypothalamus, all of which play some important roles in cognition [122]. It binds to the Gi protein to negatively control the intracellular second messenger cAMP formation by inhibition of adenylyl cyclase [123], an effect that is blocked by pre-treatment with pertussis toxin [124]. Histamine is known to downregulate the acetylcholine-induced calcium signaling of the muscarinic receptor via H3R-mediated mechanisms [125]. It also activates PLA2 and inhibits Na+/H+ exchanger activity [126]. Previous reports show that H3R in transfected SK-N-MC cells and primary cultures of cortical neurons activates the Akt/GSK-3b axis through phosphoinositol-3-kinase (PI3K) via a PTX-sensitive G i/o-protein-dependent, but Src and epidermal growth factor receptor (EGFR)-independent pathway [127] Also, treatment of transfected COS-7 and CHO cells with an agonist resulted in the rapid activation of ERK1/2, even though the underlying molecular mechanisms regulating the H3R-mediated ERK1/2 activation remain largely unknown [126,128]. It is also reported in HEK293 cells that, upon exposure to agonists, activated H3R evoked ERK1/2 phosphorylation via PLC/PKC-, PLDs, and MMP/EGFR transactivation-dependent pathways, and that the Gβγ subunit, as dissociated from the activated Gi/o protein, plays a central role in the regulation of H3R-mediated ERK1/2 activation.
It is also known that H3R antagonists can stimulate histamine, dopamine, acetylcholine, and norepinephrine, all of which are involved in some specific cognitive aspects, making H3R antagonists important drug targets to improve cognition in dementia patients. Furthermore, H3R inverse agonists can increase histaminergic neuron activity by inhibiting the H3R-mediated suppression of histamine release in the brain, making them a target for AD treatment drug development.
Although there are recent studies that have reported the involvement of histamine in neurodegenerative diseases, such as dementia, the connection between the two is intricate, and our comprehension is still incomplete. Below are several key factors concerning the potential role of histamine in dementia progression [129,130,131].

16. Role of Histamine in the Pathogenesis of Dementia

Histamine interacts with histamine receptors, specifically H1R, H2R, H3R, and H4R (Figure 1 and Figure 2; Table 1). Cognitive deficits occur when histamine is unable to bind to the receptors. The H3R reduces histamine release in the brain, resulting in AD. Inverse agonists of H3R are crucial in counteracting the effects of histamine-induced AD [132,133].
Antagonists of H3R stimulate the production of histamine, ACh, and other neurotransmitters, thereby enhancing cognitive function. Histamine plays a role in both short- and long-term cognitive processes [134]. Recent studies indicate that the deterioration of histamine neurons is the causative factor in the development of AD. The presence of histamine in the brain improves cognitive function and memory, although the specific mechanism by which it does so remains unclear [135]. The histaminergic neuron system in the brain regulates various roles, i.e., homeostasis, learning, arousal memory, and circadian rhythms. Furthermore, certain studies explained that histamine plays a part in regulating specific behavioral tasks, although the underlying mechanism remains unclear [136]. To treat AD, various pre-clinical methods have been developed to specifically target H3R [137,138].
The development of AD is attributed to the induction of neurotoxicity by Aβ, 1-42. However, this neurotoxicity can be mitigated by histamine acting on histamine receptors (H2 and H3) [139,140]. Using H2 receptor agonists leads to a gradual reduction in AD. HIR-KO mice exhibit cognitive symptoms because of alterations in the brain levels of AChE and dopamine [141]. The involvement of H1R and H2R in cognitive function is substantiated by the presence of cognitive deficits resulting from null mutations in the genes encoding these receptors. Both H1R and H2R act like excitatory neurotransmitters, whereas H3 functions differently as an inhibitory neurotransmitter and acts as an autoreceptor and heteroreceptor. Interactions between histaminergic, peptidergic, and aminergic systems can regulate homeostatic functions like sleep-wake cycles, cognition, and synaptic plasticity [142,143,144].
Histamine receptors are involved in regulating the functional activity of dendritic cell subsets. The H2R antagonist characterizes the specific mechanisms of a histamine-induced decrease of CD1a (+) DCs, IL6, and IL10 increased production, upregulation of chemokines, expression of C5aR1 through the CD1a (−) and DC subset, and increased migration of activated DC subsets, which are stimulated by the secretion of MMP-9 and MMP-12 enzymes [145]. Store-operated calcium entry (SOCE) is the main mechanism by which DCs (dendritic cells) allow Ca2+ ions to enter. DCs that have been primed with histamine can initiate the Th2 immune response by interacting with several types of histamine receptors. Histamine-activated DCs trigger the release of calcium ions (Ca2+) from their intracellular reservoirs. Histamine elevates IL-10 levels while decreasing the IL-12p70 levels that are produced by DCs. Pretreating DCs with H1R antagonists, SOC blockers, and H4R antagonists can prevent the histamine-induced Th2 polarization of T-helper cells in the mixed responses of lymphocytes. Recent research indicates that SOCE is crucial in the Th(2) response and histamine-induced maturation of DCs through the activation of both H1R and H4R [146]. Research has demonstrated that young individuals who produce elevated levels of IL-2 and IFN-γ possess a specific type of T-cell memory called beta (1-42)-specific Th1-type T-cell memory. There is evidence indicating that as individuals age, there is a decline in the production of IFN-γ and IL-2, while there is a noticeable increase in the release of regulatory IL-10 by CD4(+) T-cells. However, despite the absence of an effector cytokine, individuals with AD can still generate IL-10 [147]. The proinflammatory cytokine IL-32 can activate nuclear factor κB and p38 mitogen-activated protein kinase (p38MAPK) pathways. IL-32 can induce histamine synthesis in human-derived core blood mast cells (HDCBMCs; Figure 1). Therefore, it can be demonstrated that IL-32 is specific to a particular species and functions in fully developed human mast cells (LAD 2 cells) [148]. Research has demonstrated that IL-32 plays a role in controlling neuroinflammatory responses in various neuronal diseases, including AD [149] (Figure 3).

17. Recently Developed Drugs for the Treatment of Dementia by Blocking H3 Receptors

Despite the well-established role of histamine in memory, the stimulation of post-synaptic H1R or H2R is not an acceptable therapeutic target to enhance memory in AD because of their associated detrimental peripheral actions in the gastrointestinal and cardiovascular systems. Thus, the presynaptic H3R is considered the most suitable therapeutic target to enhance histaminergic signaling to boost memory with little peripheral side effects, as it is mostly expressed in the mammalian brain areas involved in cognitive processes and arousal, like the hippocampus, cerebral cortex, hypothalamus, and basal ganglia [150]. The activation of H3 autoreceptors leads to the inhibition of histamine synthesis and release from histaminergic neurons, while the activation of H3 heteroreceptors leads to the inhibition of release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons [151]. Conversely, a blockade of H3 receptors with selective antagonists can increase the release of neurotransmitters involved in cognitive processes [152].
The H3R is expressed in some brain regions involved in cognition, sleep, and homeostatic modulation, including the CNS, hypothalamus, cerebral cortex, and basal ganglia [122]. It affects various signaling pathways, such as the activation of PLA2, Akt, and the MAPK, G(i/o)-dependent inhibition of adenylyl cyclase, and the inhibition of both Na+/H+ exchanger and K+-induced Ca2+ mobilization [126]. In type 1 cells of rats, H3R is responsible for the histamine attenuation of calcium signaling induced by muscarinic cholinergic receptors [153]. Generally, H3Rs serve as H3 autoreceptors modulating the synthesis and release of the central.

17.1. Thioperamide

Thioperamide (Figure 4) is a highly potent and specific antagonist of imidazole. It was primarily developed to improve wakefulness and address issues related to learning and memory. According to recent research, thioperamide, despite its hepatotoxicity, has been found to have a significant impact on patients with circadian rhythm disorders and Parkinson’s disorder (Figure 4) [154]. It can cause a strong activation of histamine release and convert histamine to N-tele-methylhistamine, competitively suppressing the conversion of N-tele-methylhistamine to N-tele-methylimidazoleacetic acid in the brains of humans and monkeys due to monoamine oxidase B [155].

17.2. Pitolisant

Pitolisant (also called BF2.649 or tiprolisant) with full name [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride] is a high-affinity, competitive antagonist, and potent inverse agonist of the H3R [156] that has been approved by regulatory agencies in the United States and Europe. Its high oral bioavailability allows easy access to the brain. It undergoes metabolism by the enzyme CYP4A in the gastrointestinal tract. It is employed in managing narcolepsy to sustain wakefulness during the daytime. Headache, anxiety, and QT prolongation have been documented as adverse effects in clinical trials [157,158]. Wakix is a proprietary name for a product that has been commercially available since March 2016. The dosage is available in tablets of 4.5 mg and 18 mg. Pitolisant increases working memory using two-trial object recognition tasks [156] and fear conditioning tests.
  • GSK189254
The compound GSK189254, a high-affinity H3R antagonist, has shown therapeutic potential for AD in both rats and humans [159]. It potently inhibits cortical ex vivo H3 receptor binding, consistent with good CNS penetration and H3 receptor occupancy, and increased cortical neuronal activation [160]. A microdialysis study with GSK189254 showed increases in acetylcholine, noradrenaline, and dopamine release in the cortex, consistent with the blockade of H3 heteroreceptors. In addition, GSK189254 potently blocked H3 agonist-induced dipsogenia, consistent with the functional blockade of H3 receptors in vivo. It was also shown to reverse the amnesia induced by cholinergic antagonist scopolamine. Furthermore, it had behavioral effects, where it reduced platform escape latency in aged rat water maze tests, improved task recall in probe trials, improved recognition and memory in object recognition and novelty detection tests, and improved attention reversal learning and attentional set shifting [150].
  • E177
E177 [1-(6-(naphthalen-2-yloxy)hexyl)azepane hydrogen oxalate] is a non-imidazole-based H3R antagonist E177, with high antagonist affinity (Ki = 69.40 nM) and high in vitro selectivity. It was shown to mitigate dizocilpine-induced cognitive impairments via the modulation of histaminergic neurotransmission [161].
  • SAR110894
SAR110894 has been shown to prevent episodic memory deficits induced by scopolamine in rats or by the central infusion of the toxic amyloid fragment Aβ (25–35) in the object recognition test in mice. Its acute treatment improves cognition in several animal models displaying cognitive deficits relevant to those found in patients with AD [162]. Chronic administration of SAR110894 in a transgenic mouse model of tauopathy prevents cognitive deficits and inhibits tau pathology [162].
  • ABT-239
ABT-239 stimulates biochemical signaling that improves cognitive performance and attenuates tau hyperphosphorylation [160].
  • E169
E169 [1-(6-(naphthalen-1-yloxy)hexyl)azepane] is a newly developed, highly potent and selective non-imidazole H3R antagonist with high affinity [161]. Studies have reported the ADMET properties, in silico docking to human H3R, and in vivo memory-enhancing effects of E169 [161]. This agent has a high dG bind value of −108.24 kcal/mol and occupies the H3R binding pocket like the resolved complex ligand PF03654746, establishing the interaction of a crucial histamine H3R antagonist/inverse agonist like salt bridge and/or hydrogen bond formation between protonated amine nitrogen and ASP1143.32 [Levoin et al., 2008], and west-end stabilization with caging the aromatic sidechains of Y1153.33, F3987.39, and Y3746.51 [162]. The east-end naphthalene substituent of E169 occupied the space fenced by aromatic features of TYR189 (ECL2) on the top, and TYR912.61 and TYR942.64 on the sides that also stabilized the structure through Π–Π stacking interactions (Figure 5). A recent study with mice showed that E169 ameliorated MK801-induced reduction in the short- and long-term memory and the disturbance in neurochemicals, including PI3K, Akt, and GSK-3β in the hippocampus [162], suggesting it as a candidate for H3R in the treatment of AD.

18. Conclusions

Neuropharmacology has a lot of potential as H3R modulators are being used to treat dementia after being experimentally developed. Investigating these modulators has yielded valuable understandings of the intricate mechanisms that underlie dementia and has unveiled fresh prospects for therapeutic interventions. The bench-to-bedside approach prioritizes the smooth conversion of scientific findings into tangible implementations for patient treatment.
The combined endeavors of researchers, clinicians, and pharmaceutical developers are instrumental in creating groundbreaking solutions that could revolutionize dementia treatment in the future. As research and clinical trials progress, our understanding of H3 receptor modulators will improve, leading to a better understanding of their role in the comprehensive care and management of dementia patients.

19. Future Prospective

While H3R modulators seem to be promising potential therapeutic agents for dementia, further research and development efforts are needed to realize their full clinical potential and impact on patient outcomes. Collaboration between academia, industry, regulatory agencies, and patient advocacy groups will be essential in advancing this field and addressing the growing burden of dementia worldwide.

Author Contributions

N.B., S.P.N.B., and H.O.: Conceptualized, designed, and coordinated the work, writing-original draft preparation; V.M.D.P., G.S., H.O., and V.S.S.: Manuscript review, revision, and reference work; S.N. and P.B.D.: Manuscript review and revision; S.P.N.B., A.I.A., J.O.C.E., and H.O.: Coordination work, figure generation, writing-review and editing, manuscript revision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no any external funding.

Data Availability Statement

Data used in this study are available within the manuscript.

Conflicts of Interest

All authors report that there was no conflict of interest in this work.

Abbreviations

Aβ: Amyloid-beta protein; AC: adenylyl cyclase; AD: Alzheimer’s Disease; AKT: protein kinase B; APOE4: Apolipoprotein E Ɛ 4 gene carrier; APP: Amyloid Precursor Protein, BACE: Beta site cleavage enzyme; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; DC: Dendritic cells; ERK, extracellular signal-regulated kinase; H1R, histamine receptor subtype 1; H2R, histamine receptor subtype 2; H3R, histamine receptor subtype 3; H4R, histamine receptor subtype 4; HDCBMC: human-derived core blood mast cells; MAPK, mitogen-activated protein kinase; p38MAPK: p38 mitogen activated protein kinase; PKA: protein kinase A; PKC: protein kinase C; PLA2: phospholipase A2; PLC: Phospholipase C; Rac, Ras-related C3 botulinum toxin substrate; RhoA, Ras homolog family member A; SOCE: Store-Operated Calcium Entry.

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Figure 1. Overview of Histamine Regulation.
Figure 1. Overview of Histamine Regulation.
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Figure 2. Histamine receptors—Signaling pathways.
Figure 2. Histamine receptors—Signaling pathways.
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Figure 3. Role of histamine in neuronal development.
Figure 3. Role of histamine in neuronal development.
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Figure 4. Structure of Thioperamide.
Figure 4. Structure of Thioperamide.
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Figure 5. (Left panel): Putative binding mode of E169 (left) in the histamine H3R binding site. Yellow dashed lines denote hydrogen bonds, magenta denotes salt bridges, green denotes cation-Π interactions, and blue denotes Π-ΠΠ interactions, while Roman numbers denote respective TMs. (Right panel): MD stimulation of ligand-protein contact summary (top), and contacts histogram (bottom: green—H-bond; violet—hydrophobic contact; blue—water bridges).
Figure 5. (Left panel): Putative binding mode of E169 (left) in the histamine H3R binding site. Yellow dashed lines denote hydrogen bonds, magenta denotes salt bridges, green denotes cation-Π interactions, and blue denotes Π-ΠΠ interactions, while Roman numbers denote respective TMs. (Right panel): MD stimulation of ligand-protein contact summary (top), and contacts histogram (bottom: green—H-bond; violet—hydrophobic contact; blue—water bridges).
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Table 1. Characteristics of Histamine Receptors.
Table 1. Characteristics of Histamine Receptors.
S.NoTypeLocationFunctionBinding Affinity to
Histamine (pKi)		Signaling
Pathway
(Figure 2)		Ref.
CentralPeripheral
1H1RForebrain, cerebral cortex,
Hippocampus, and
Thalamus		Heart and smooth musclesDecreasing blood pressure, inflammatory response, and increased wakefulness4.2Phospholipase C (PLC)[132]
2H2RSubstantia Nigra, raphe nuclei, Hippocampus, and basal gangliaIntestinal smooth muscles, heart, and lungs Regulation of hormone release, fluid balance, excitation, relaxation of airway smooth muscles, blood pressure regulation, and gastric acid regulation4.3Protein kinase C (PKC) activation [132]
3H3RCerebral cortex, basal ganglia, and hypothalamusLung, cardiovascular system (CVS), and intestineHistamine release, regulation, and stimulation8.0Inhibition of protein kinase A (PKA),
activation of
Phospholipase 2, mitogen-activated protein kinase (MAPK)		[133]
4H4RCerebellum and HippocampusHematopoietic cells Modulation of the Immune system7.8PKA Inhibition,
PLC and MAPK activation		[133]
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Bandaru, N.; Bukke, S.P.N.; Pedapati, V.M.D.; Sowjanaya, G.; Suggu, V.S.; Nalla, S.; Dudhe, P.B.; Ezeonwumelu, J.O.C.; Alagbonsi, A.I.; Onohuean, H. Pathophysiology of Alzheimer’s Disease: Focus on H3 Receptor Modulators and Their Implications. Drugs Drug Candidates 2025, 4, 22. https://doi.org/10.3390/ddc4020022

AMA Style

Bandaru N, Bukke SPN, Pedapati VMD, Sowjanaya G, Suggu VS, Nalla S, Dudhe PB, Ezeonwumelu JOC, Alagbonsi AI, Onohuean H. Pathophysiology of Alzheimer’s Disease: Focus on H3 Receptor Modulators and Their Implications. Drugs and Drug Candidates. 2025; 4(2):22. https://doi.org/10.3390/ddc4020022

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Bandaru, Nagaraju, Sarad Pawar Naik Bukke, Veera Mani Deepika Pedapati, Gurugubelli Sowjanaya, Vangmai Swaroopa Suggu, Swathi Nalla, Prashik Bhimrao Dudhe, Joseph Obiezu Chukwujekw Ezeonwumelu, Abdullateef Isiaka Alagbonsi, and Hope Onohuean. 2025. "Pathophysiology of Alzheimer’s Disease: Focus on H3 Receptor Modulators and Their Implications" Drugs and Drug Candidates 4, no. 2: 22. https://doi.org/10.3390/ddc4020022

APA Style

Bandaru, N., Bukke, S. P. N., Pedapati, V. M. D., Sowjanaya, G., Suggu, V. S., Nalla, S., Dudhe, P. B., Ezeonwumelu, J. O. C., Alagbonsi, A. I., & Onohuean, H. (2025). Pathophysiology of Alzheimer’s Disease: Focus on H3 Receptor Modulators and Their Implications. Drugs and Drug Candidates, 4(2), 22. https://doi.org/10.3390/ddc4020022

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