New Drug Delivery Systems Developed for Brain Targeting

Rawal, Shruti; Patel, Bhoomika M.; Patel, Mayur M.

doi:10.1007/s40265-022-01717-z

Cited by 24 publications

(6 citation statements)

References 286 publications

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“…The present study demonstrates for the first time that GALR2 and Y1R agonists intranasal infusion stimulates adult ventral hippocampal neurogenesis and exerts an antidepressant‐like effect. Intranasal delivery offers an alternative to icv infusion to bypass the blood–brain barrier for the direct delivery of peptides and protein therapeutics rapidly into the CNS, supported by robust evidence in preclinical and clinical trials (Lochhead & Thorne, 2012 ; Rawal et al, 2022 ). This method will be crucial as novel therapies continue to be studied in clinical trials and have several benefits, such as fewer side effects than peripheral administration and the comfort of noninvasiveness application (Chapman et al, 2013 ; Crowe & Hsu, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant‐like effects involving BDNF actions

Alvarez-Contino

Díaz-Sánchez

Mirchandani-Duque

et al. 2023

Journal Cellular Physiology

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Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID‐19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular‐, cellular‐, and behavioral‐specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain‐derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R–GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R–GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant‐like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R–GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive‐affecting diseases.

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Section: Discussionmentioning

confidence: 99%

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant‐like effects involving BDNF actions

Alvarez-Contino

Díaz-Sánchez

Mirchandani-Duque

et al. 2023

Journal Cellular Physiology

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“…The BBB constitutes an obstacle for the delivery of therapeutic drugs into the brain ( 38 ). As one of the most active transcytosis pathways in HBMECs, TfR transcytosis has been extensively studied for drug transport, and some approaches using TfR-targeting antibodies and antibody-drug conjugates for delivery across the BBB have shown promising results in clinical trials ( 13 , 38 , 46 ). As a result of host and pathogen coevolution, major pathogenic bacteria exploit the same TfR transcytosis pathway to traverse the BBB.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier

Cheng,

Zheng,

Yang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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The human blood–brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae , group B Streptococcus , and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.

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“…Though it shows little toxicity, overexposure to it may be deadly or can cause death 184 . To prevent liver toxicity and non-specific side effects, strategies like targeted NF-κB inhibition, direct delivery systems like nanoparticles or antibody-drug conjugates, combination therapy, dose optimization based on individual factors like disease severity and genetic variations, and biomarkers can be employed 185 , 186 . These strategies aim to minimize off-target effects, reduce systemic exposure and side effects, enhance efficacy, and minimize side effects while maintaining therapeutic efficacy 187 .…”

Section: Toxicity Of Polyphenolsmentioning

confidence: 99%

Polyphenols Targeting NF-κB Pathway in Neurological Disorders: What We Know So Far?

Mamun,

Shao,

Geng

et al. 2024

Int. J. Biol. Sci.

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Polyphenolic compounds have shown promising neuroprotective properties, making them a valuable resource for identifying prospective drug candidates to treat several neurological disorders (NDs). Numerous studies have reported that polyphenols can disrupt the nuclear factor kappa B(NF-κB) pathway by inhibiting the phosphorylation or ubiquitination of signaling molecules, which further prevents the degradation of IκB. Additionally, they prevent NF-κB translocation to the nucleus and pro-inflammatory cytokine production. Polyphenols such as curcumin, resveratrol, and pterostilbene had significant inhibitory effects on NF-κB, making them promising candidates for treating NDs. Recent experimental findings suggest that polyphenols possess a wide range of pharmacological properties. Notably, much attention has been directed towards their potential therapeutic effects in NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety, depression, autism, and spinal cord injury (SCI). Much preclinical data supporting the neurotherapeutic benefits of polyphenols has been developed. Nevertheless, this study has described the significance of polyphenols as potential neurotherapeutic agents, specifically emphasizing their impact on the NF-κB pathway. This article offers a comprehensive analysis of the involvement of polyphenols in NDs, including both preclinical and clinical perspectives.

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New Drug Delivery Systems Developed for Brain Targeting

Cited by 24 publications

References 286 publications

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant‐like effects involving BDNF actions

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant‐like effects involving BDNF actions

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier

Polyphenols Targeting NF-κB Pathway in Neurological Disorders: What We Know So Far?

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