5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats

With the increasing aging population and progressive nature of the disease, Alzheimer’s disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

show abstract

“…On the 6th day, surgery was performed as described (Bokare et al 2018 ). Rat was anesthetized with sodium pentobarbital (45 mg/kg, i.p.)…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease

Rompicherla

Karthik

Bojja

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

show abstract

“…On 6th day, surgery was performed as described [16]. Rat was anesthetized with sodium pentobarbital (45 mg/kg, i.p.)…”

Section: Icv Colchicine Induced Dementiamentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Evaluation of Nasal Liposome and Nanoparticle Based Rivastigmine Formulations in Acute and Chronic Models of Alzheimer’s Disease

Rompicherla¹,

Karthik²,

Bojja³

et al. 2021

Preprint

View full text Add to dashboard Cite

With the increasing ageing population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor is more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing first pass metabolism, exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver efficiently to brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in scopolamine induced amnesia model and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modelling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax=5 minutes), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F=118.65 ± 23.54; AUC= 35921.75 ± 9559.46), increased half-life (30.92 ± 8.38 minutes), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax= 15 minutes; Cmax= 56.29 ± 27.05; F=4.39 ± 1.82; AUC=1663.79 ± 813.54; t1/2= 13.48 ± 5.79; Kel (1/min) =0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modelling demonstrated strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

show abstract

“…Notably, these conflicting results come from studies that have investigated the effect of agonists on healthy animals. When used in models of cognitive impairment, EMD386088 as well as WAY181187 have been shown to improve memory in the same way as antagonists (Bokare et al, 2018;Nikiforuk et al, 2013;Rychtyk et al, 2019). EMD386088 also reverses cognitive deficits in a rat model of schizophrenia (ketamine treatment) (Nikiforuk et al, 2013).…”

Section: Agonistsmentioning

confidence: 99%

The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies

et al. 2020

View full text Add to dashboard Cite

The serotonin (5-HT) 6 receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively located in the primary cilium of neurons. The 5-HT 6 receptor continues to raise particular interest for neuropharmacologists, given the pro-cognitive effects of antagonists in a wide range of cognitive impairment paradigms in rodents and human. The 5-HT 6 receptor also finely controls key neuro-developmental processes including neuron migration and differentiation.However, its influence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggesting alternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT 6 receptor one of the G proteincoupled receptors with the most extensively characterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, are finely modulated by several receptor partners. They demonstrated that prefrontal 5-HT 6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT 6 -mTOR pathway in temporal epilepsy. Finally, they revealed that the receptor activates Cdk5 signaling in an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key role in the migration of neurons and neurite growth.These new receptor-operated signaling mechanisms should be considered in the future development of drugs acting on 5-HT 6 receptors.

show abstract

5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats

Abstract: The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.

Cited by 20 publications

References 53 publications

Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease

Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease

Pharmacokinetic and Pharmacodynamic Evaluation of Nasal Liposome and Nanoparticle Based Rivastigmine Formulations in Acute and Chronic Models of Alzheimer’s Disease

The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies

Contact Info

Product

Resources

About