Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer’s disease

Chintamaneni, Pavan Kumar; Krishnamurthy, Praveen Thaggikuppe; Rao, P. Vengal

doi:10.1016/j.mehy.2017.01.026

Cited by 14 publications

(8 citation statements)

References 54 publications

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“…For that reason, new strategies are pursued in the therapy of Alzheimer’s disease to selectively activate the M 1 receptor. Examples are the development of highly selective agonists for the M 1 receptor subtype 10 or the use of positive allosteric modulators, which selectively enhance M 1 receptor affinity to acetylcholine 11,12 .…”

Section: Introductionmentioning

confidence: 99%

The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice

Laspas

Zhutdieva

Brochhausen

et al. 2019

Sci Rep

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Muscarinic acetylcholine receptors have been implicated as potential neuroprotective targets for glaucoma. We tested the hypothesis that the lack of a single muscarinic receptor subtype leads to age-dependent neuron reduction in the retinal ganglion cell layer. Mice with targeted disruption of single muscarinic acetylcholine receptor subtype genes (M1 to M5) and wild-type controls were examined at two age categories, 5 and 15 months, respectively. We found no differences in intraocular pressure between individual mouse groups. Remarkably, in 15-month-old mice devoid of the M1 receptor, neuron number in the retinal ganglion cell layer and axon number in the optic nerve were markedly reduced. Moreover, mRNA expression for the prooxidative enzyme, NOX2, was increased, while mRNA expression for the antioxidative enzymes, SOD1, GPx1 and HO-1, was reduced in aged M1 receptor-deficient mice compared to age-matched wild-type mice. In line with these findings, the reactive oxygen species level was also elevated in the retinal ganglion cell layer of aged M1 receptor-deficient mice. In conclusion, M1 receptor deficiency results in retinal ganglion cell loss in aged mice via involvement of oxidative stress. Based on these findings, activation of M1 receptor signaling may become therapeutically useful to promote retinal ganglion cell survival.

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Section: Introductionmentioning

confidence: 99%

The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice

Laspas

Zhutdieva

Brochhausen

et al. 2019

Sci Rep

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“…The formulation was found to be safe for nasal administration in an in vitro nasal ciliotoxicity investigation. After nasal injection, in vivo biodistribution showed that pioglitazone-loaded NLC delivered more pioglitazone to the brain, suggesting the potential of NLC as an effective pioglitazone carrier in AD therapy ( Chintamaneni et al, 2017 ).…”

Section: Nanocarrier-based Systems For Management Of Alzheimer’s Dise...mentioning

confidence: 99%

“…The bioavailability of these PAMs in the brain is one of their primary drawbacks. The bioavailability of PAMs of the M1 receptor has been found to be improved by surface-modified nano-LDCs ( Chintamaneni et al, 2017 ). When used in conjunction with AChE inhibitors, they are predicted to improve the effectiveness while lowering therapeutic dose and adverse effects.…”

Section: Nanocarrier-based Systems For Management Of Alzheimer’s Dise...mentioning

confidence: 99%

Nasal delivery of neurotherapeutics via nanocarriers: Facets, aspects, and prospects

Rajput

Dhapte‐Pawar

2022

Front. Pharmacol.

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Alzheimer’s disease (AD) is one of the neurological ailments which continue to represent a major public health challenge, owing to increased life expectancy and aging population. Progressive memory loss and decrease in cognitive behavior, owing to irreversible destruction of neurons along with expensive therapeutic interventions, call for an effective, alternate, yet affordable treatment for Alzheimer’s disease. Safe and effective delivery of neurotherapeutics in Alzheimer’s like central nervous system (CNS) disorders still remains elusive despite the major advances in both neuroscience and drug delivery research. The blood–brain barrier (BBB) with its tight endothelial cell layer surrounded by astrocyte foot processes poses as a major barrier for the entry of drugs into the brain. Nasal drug delivery has emerged as a reliable method to bypass this blood–brain barrier and deliver a wide range of neurotherapeutic agents to the brain effectively. This nasal route comprises the olfactory or trigeminal nerves originating from the brain and terminating into the nasal cavity at the respiratory epithelium or olfactory neuroepithelium. They represent the most direct method of noninvasive entry into the brain, opening the most suitable therapeutic avenue for treatment of neurological diseases. Also, drugs loaded into nanocarriers can have better interaction with the mucosa that assists in the direct brain delivery of active molecules bypassing the BBB and achieving rapid cerebrospinal fluid levels. Lipid particulate systems, emulsion-based systems, vesicular drug delivery systems, and other nanocarriers have evolved as promising drug delivery approaches for the effective brain delivery of anti-Alzheimer’s drugs with improved permeability and bioavailability via the nasal route. Charge, size, nature of neurotherapeutics, and formulation excipients influence the effective and targeted drug delivery using nanocarriers via the nasal route. This article elaborates on the recent advances in nanocarrier-based nasal drug delivery systems for the direct and effective brain delivery of the neurotherapeutic molecules. Additionally, we have attempted to highlight various experimental strategies, underlying mechanisms in the pathogenesis and therapy of central nervous system diseases, computational approaches, and clinical investigations pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain via the nose-to-brain route, using nanocarriers.

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“…18,19 Alternately, positive allosteric modulators (PAMs) of M 1 AChRs such as benzyl quinolone carboxylic acid (BQCA) can help in specic activation of M 1 AChRs. [20][21][22] PAMs through their selective binding at allosteric site of M 1 mAChR lead to conformational changes in M 1 mAChR. This facilitates enhanced binding of the orthosteric ligand, ACh, to the M 1 mAChR, thus, selectively increasing the actions of endogenous ACh on M 1 receptor over M 2 -M 5 receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…PAMs, however, suffer from low brain half-life and faster elimination rates. [22][23][24] The brain bioavailability of PAMs can be signicantly improved by formulating them as lipid drug conjugates (LDCs). 25 LDCs improve the lipophilic characteristics of a drug and have high drug loading capacity.…”

Section: Introductionmentioning

confidence: 99%

Polysorbate-80 surface modified nano-stearylamine BQCA conjugate for the management of Alzheimer's disease

Chintamaneni

Krishnamurthy

2021

RSC Adv.

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Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer’s disease

Cited by 14 publications

References 54 publications

The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice

The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice

Nasal delivery of neurotherapeutics via nanocarriers: Facets, aspects, and prospects

Polysorbate-80 surface modified nano-stearylamine BQCA conjugate for the management of Alzheimer's disease

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