REMOVED: 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

Sharma, Aruna; Mureșanu, Dafin F.; Patnaik, Ranjana; Menon, Preeti; Tian, Z. Ryan; Sahib, Seaab; Castellani, Rudy J.; Nozari, Ala; Lafuente, José Vicente; Skaper, Stephen D.; Bryukhovetskiy, Igor; Manzhulo, Igor; Wiklund, Lars; Sharma, Hari Shanker

doi:10.1016/bs.pbr.2021.06.003

Cited by 21 publications

(9 citation statements)

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“…Currently, increasing attention is paid to the signaling of the biogenic amine histamine in the context of several pathological conditions such as Parkinson’s disease [ 6 ], sleep disorders, schizophrenia, cerebral ischemia [ 7 ], amyotrophic lateral sclerosis (ALS) [ 8 ], Alzheimer’s disease [ 9 ] or physiological conditions of the CNS, such as memory [ 10 , 11 ] and neurodevelopment [ 12 ]. Regarding MS, it is well established that histamine is directly involved in the disease, for instance by regulating the differentiation of oligodendrocyte precursors, reducing demyelination, and improving the remyelination process [ 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Repurposing Histaminergic Drugs in Multiple Sclerosis

Amadio

Conte

Esposito

et al. 2022

IJMS

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Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1–H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.

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Section: Introductionmentioning

confidence: 99%

Repurposing Histaminergic Drugs in Multiple Sclerosis

Amadio

Conte

Esposito

et al. 2022

IJMS

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“…However, the relief of the motor symptoms by such therapy is only temporary and other symptoms of PD do not respond to dopaminergic therapy at all. 14 More effective treatments may be developed by targeting more than a single neurotransmitter pathway and by considering both the motor and nonmotor complications of PD. Such therapies could be based on the administration of multiple drugs, or a single molecule interacting with multiple targets.…”

Section: Introductionmentioning

confidence: 99%

“… 6 , 7 , 19 − 22 There is evidence that the administration of an H 3 receptor antagonist can potentially ameliorate various symptoms in PD. 13 , 14 , 23 , 24 Based on preclinical studies in animals and humans, several H 3 antagonists have been proposed as a treatment for cognitive impairment. 25 − 35 This concept could also be important for the treatment of PD, since cognitive impairment is a major nonmotor symptom in PD patients, with a prevalence rate 3 times higher than in the general population.…”

Section: Introductionmentioning

confidence: 99%

“…These strategies address the dopaminergic deficit, thus providing relief of the motor symptoms. However, the relief of the motor symptoms by such therapy is only temporary and other symptoms of PD do not respond to dopaminergic therapy at all . More effective treatments may be developed by targeting more than a single neurotransmitter pathway and by considering both the motor and nonmotor complications of PD.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the dopamine D 2 receptor, the histamine-3 (H 3 ) receptor has received particular attention since it acts as a modulator in the release of various neurotransmitters that are involved in the pathophysiology of PD. ,,− There is evidence that the administration of an H 3 receptor antagonist can potentially ameliorate various symptoms in PD. ,,, Based on preclinical studies in animals and humans, several H 3 antagonists have been proposed as a treatment for cognitive impairment. − This concept could also be important for the treatment of PD, since cognitive impairment is a major nonmotor symptom in PD patients, with a prevalence rate 3 times higher than in the general population. − …”

Section: Introductionmentioning

confidence: 99%

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Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats

et al. 2022

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Introduction : Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D 2 /D 3 agonist/H 3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D 2 /D 3 receptor ligand [ 11 C]raclopride or the histamine H 3 receptor ligand [ 11 C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [ 11 C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [ 11 C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution ( V T ) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results : Dopamine D 2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V T values of [ 11 C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H 3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions : Target engagement of AG-0029 as an agonist at dopamine D 2 /D 3 receptors and an antagonist at histamine H 3 receptors could be demonstrated in the rat brain with [ 11 C]raclopride and [ 11 C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D 2 /D 3 and moderate (submicromolar) affinity to H 3 receptors.

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Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation

Sharma¹,

Feng²,

Mureșanu³

et al. 2023

Advances in Neurobiology

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REMOVED: 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

Cited by 21 publications

References 307 publications

Repurposing Histaminergic Drugs in Multiple Sclerosis

Repurposing Histaminergic Drugs in Multiple Sclerosis

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation

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REMOVED: 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

Cited by 21 publications

References 307 publications

Repurposing Histaminergic Drugs in Multiple Sclerosis

Repurposing Histaminergic Drugs in Multiple Sclerosis

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation

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Product

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Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats