AAV9-Retro Mediates Efficient Transduction with Axon Terminal Absorption and Blood-brain Barrier Transportation

Abstract Recombinant adeno-associated viruses (rAAVs), particularly those that permit efficient gene transfer to neurons from axonal terminals or across the blood–brain barrier, are useful vehicles for structural and functional studies of the neural circuit and for the treatment of many gene-deficient brain diseases that need to compensate for the correct genes in every cell in the whole brain. However, AAVs with these two advantages have not been reported. Here, we describe a new capsid engineering method, which exploits the combination of different capsids and aims to yield a capsid that can provide more alternative routes of administration that are more suitable for the wide-scale transduction of the central nervous system (CNS). A new AAV variant, AAV9-Retro, was developed by inserting the 10-mer peptide fragment from AAV2-Retro into the capsid of AAV9, and the biodistribution properties were evaluated in mice. By intracranial and intravenous injection in the mice, we found that AAV9-Retro can retrogradely infect projection neurons with an efficiency comparable to that of AAV2-Retro and retains the characteristic of AAV9, which can be transported across the nervous system. Our strategy provides a new tool for the manipulation of neural circuits and future preclinical and clinical treatment of some neurological and neurodegenerative disorders.

Download Full-text

AAV9-Retro mediates efficient transduction with axon terminal absorption and blood–brain barrier transportation

Molecular Brain ◽

10.1186/s13041-020-00679-1 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Kunzhang Lin ◽

Xin Zhong ◽

Lei Li ◽

Min Ying ◽

Tian Yang ◽

...

Keyword(s):

Nervous System ◽

Blood Brain Barrier ◽

Neural Circuit ◽

Brain Barrier ◽

Brain Diseases ◽

Projection Neurons ◽

Routes Of Administration ◽

Functional Studies ◽

Blood Brain ◽

Alternative Routes

Abstract Recombinant adeno-associated viruses (rAAVs), particularly those that permit efficient gene transfer to neurons from axonal terminals or across the blood–brain barrier, are useful vehicles for structural and functional studies of the neural circuit and for the treatment of many gene-deficient brain diseases that need to compensate for the correct genes in every cell in the whole brain. However, AAVs with these two advantages have not been reported. Here, we describe a new capsid engineering method, which exploits the combination of different capsids and aims to yield a capsid that can provide more alternative routes of administration that are more suitable for the wide-scale transduction of the central nervous system (CNS). A new AAV variant, AAV9-Retro, was developed by inserting the 10-mer peptide fragment from AAV2-Retro into the capsid of AAV9, and the biodistribution properties were evaluated in mice. By intracranial and intravenous injection in the mice, we found that AAV9-Retro can retrogradely infect projection neurons with an efficiency comparable to that of AAV2-Retro and retains the characteristic of AAV9, which can be transported across the nervous system. Our strategy provides a new tool for the manipulation of neural circuits and future preclinical and clinical treatment of some neurological and neurodegenerative disorders.

Download Full-text

Blood-Brain Barrier Transport of Drugs for the Treatment of Brain Diseases

CNS & Neurological Disorders - Drug Targets ◽

10.2174/187152709788680652 ◽

2009 ◽

Vol 8 (3) ◽

pp. 195-204 ◽

Cited By ~ 27

Author(s):

Reinhard Gabathuler

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain

Download Full-text

Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

International Journal of Molecular Sciences ◽

10.3390/ijms22073356 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3356

Author(s):

Manon Leclerc ◽

Stéphanie Dudonné ◽

Frédéric Calon

Keyword(s):

Natural Products ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Omega 3 ◽

Indirect Pathway ◽

Brain Functions ◽

Blood Brain ◽

The Central Nervous System ◽

Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

Download Full-text

Gastrodia-Uncaria Water Extract Inhibits Endoplasmic Reticulum Stress and Matrix Metalloproteinase in Protecting against Cerebral Ischemia

10.1101/2021.07.21.452303 ◽

2021 ◽

Author(s):

Angus Y Choi ◽

Jia Wen Xian ◽

Sum Yi Ma ◽

Zhixiu Lin ◽

Chun Wai Chan

Keyword(s):

Endoplasmic Reticulum ◽

Cerebral Ischemia ◽

Endoplasmic Reticulum Stress ◽

Blood Brain Barrier ◽

Neuroprotective Effect ◽

Water Extract ◽

Neuronal Cell ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain

Stroke is the second leading cause of death in worldwide, in which cerebral ischemia accounts for 87% of all cases. The building up of endoplasmic reticulum stress in cerebral ischemia contributes to the disruption of blood brain barrier and neuronal cell death. The only FDA-approved drug, recombinant tissue plasminogen activator, is still of limited use due to the narrow window period and lack of neuroprotective effect. Therefore, it is necessary to explore alternative treatment on cerebral ischemia. Tianma-Gouteng decoction is a traditional Chinese Medicine prescription used to treat brain diseases in China. In this study, we investigated the neuroprotective effect of a water extract consisting of Gastrodia elata and Uncaria rhynchophylla, which are the two main herbs in the decoction. Cerebral ischemia was induced in rats using middle cerebral artery occlusion. GUW-treated rats have significantly reduced infarction volume and recovered neurological functions. The number of protein aggregates and caspase-12 positive cells were significantly inhibited. In vitro oxygen-glucose deprivation / reoxygenation stroke model demonstrated that the unfolded protein response proteins GRP78 and PDI were upregulated by GUW. Less ubiquitin puncta and normalized ubiquitin distribution indicated the reduction in endoplasmic reticulum stress. Furthermore, a lower Evan blue signal and MMPsense signal was observed, suggesting that GUW may preserve the blood brain barrier integrity through inhibiting MMP activity. Taken together, this suggested that GUW protected ischemic neurons and the blood brain barrier through inhibiting endoplasmic reticulum stress.

Download Full-text

Targeting microRNAs to Regulate the Integrity of the Blood–Brain Barrier

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.673415 ◽

2021 ◽

Vol 9 ◽

Author(s):

Juntao Wang ◽

Fang Xu ◽

Xiaoming Zhu ◽

Xianghua Li ◽

Yankun Li ◽

...

Keyword(s):

Blood Brain Barrier ◽

Neurovascular Unit ◽

Cerebrovascular Diseases ◽

Brain Parenchyma ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain ◽

Recent Developments ◽

Important Regulator

The blood–brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.

Download Full-text

Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2936737 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Zi-xian Chen ◽

Qing-qing Xu ◽

Chun-shuo Shan ◽

Yi-hua Shi ◽

Yong Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Ischemic Injury ◽

Brain Barrier ◽

Brain Diseases ◽

Glycoprotein P ◽

Blood Brain ◽

Cerebral Ischemic Injury ◽

Bbb Permeability ◽

Cerebral Ischemic

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P<0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

Download Full-text

Photodynamic Opening of the Blood–Brain Barrier Using Different Photosensitizers in Mice

Applied Sciences ◽

10.3390/app10010033 ◽

2019 ◽

Vol 10 (1) ◽

pp. 33 ◽

Cited By ~ 1

Author(s):

Oxana Semyachkina-Glushkovskaya ◽

Ekaterina Borisova ◽

Vanya Mantareva ◽

Ivan Angelov ◽

Ivelina Eneva ◽

...

Keyword(s):

Tight Junction ◽

Blood Brain Barrier ◽

Confocal Imaging ◽

Brain Barrier ◽

Zinc Phthalocyanine ◽

Brain Diseases ◽

Blood Brain ◽

Age Related ◽

Dextran 70 ◽

The Brain

In a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood–brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB to EBAC and FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases.

Download Full-text

Neurological Diseases in Relation to the Blood–Brain Barrier

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.197 ◽

2012 ◽

Vol 32 (7) ◽

pp. 1139-1151 ◽

Cited By ~ 226

Author(s):

Gary A Rosenberg

Keyword(s):

Free Radicals ◽

Blood Brain Barrier ◽

Neurological Diseases ◽

Neurovascular Unit ◽

Brain Barrier ◽

Cellular Damage ◽

Brain Diseases ◽

Acute Injury ◽

Blood Brain ◽

The Brain

Disruption of the blood–brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.

Download Full-text