Noninvasive Brain Delivery and Efficacy of BDNF to Stimulate Neuroregeneration and Suppression of Disease Relapse in EAE Mice

Abstract

The number of FDA-approved protein drugs (biologics), such as antibodies, antibody−drug conjugates, hormones, and enzymes, continues to grow at a rapid rate; most of these drugs are used to treat diseases of the peripheral body. Unfortunately, most of these biologics cannot be used to treat brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and brain tumors in a noninvasive manner due to their inability to permeate the blood−brain barrier (BBB). Therefore, there is a need to develop an effective method to deliver protein drugs into the brain. Here, we report a proof of concept to deliver a recombinant brain-derived neurotrophic factor (BDNF) to the brains of healthy and experimental autoimmune encephalomyelitis (EAE) mice via intravenous (iv) injections by co-administering BDNF with a BBB modulator (BBBM) peptide ADTC5. Western blot evaluations indicated that ADTC5 enhanced the brain delivery of BDNF in healthy SJL/elite mice compared to BDNF alone and triggered the phosphorylation of TrkB receptors in the brain. The EAE mice treated with BDNF + ADTC5 suppressed EAE relapse compared to those treated with BDNF alone, ADTC5 alone, or vehicle. We further demonstrated that brain delivery of BDNF induced neuroregeneration via visible activation of oligodendrocytes, remyelination, and ARC and EGR1 mRNA transcript upregulation. In summary, we have demonstrated that ADTC5 peptide modulates the BBB to permit noninvasive delivery of BDNF to exert its neuroregeneration activity in the brains of EAE mice.

Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice

“…Furthermore, there were significant increases in the expression of NG2 cells (Figure 4) as well as EGR1 and ARC mRNA transcripts ( Figure 5) remission prevented the disease relapse as determined by the disease body scores while multiple treatments of EAE mice with BDNF alone, ADTC5 alone, or vehicle alone did not prevent the disease relapse. 29 Similarly, EAE mice treated with BDNF + ADTC5 promoted NG2 glia maturation, increased ARC and EGR1 expressions, and enhanced axon remyelination compared to those treated with BDNF alone or vehicle. 29 In the same study, BDNF delivered with ADTC5 was detected in the brain homogenates using Western blots while BDNF delivered alone could not be detected in the brain homogenates.…”

“…29 Similarly, EAE mice treated with BDNF + ADTC5 promoted NG2 glia maturation, increased ARC and EGR1 expressions, and enhanced axon remyelination compared to those treated with BDNF alone or vehicle. 29 In the same study, BDNF delivered with ADTC5 was detected in the brain homogenates using Western blots while BDNF delivered alone could not be detected in the brain homogenates. In addition, administration of BDNF + ADTC5 triggered phosphorylation of TrkB (pTrkB) receptors in the brain; in contrast, administration of BDNF alone did not trigger pTrkB formation.…”

“…A significant upregulation of NG2 glia cells in the corpus callosum was also observed when EAE mice were treated with BDNF + ADTC5. 29 Similarly, Nakajima et al (2010) Copyright 2020 KEI Journals. All Rights Reserved showed that targeted retrograde gene delivery of BDNF in rats after spinal cord injury suppressed apoptosis of neurons and oligodendroglia, which resulted in a significant promotion of NG2 expression.…”

“…28 Recently, multiple treatments of experimental autoimmune encephalomyelitis (EAE) mice (an animal model of multiple sclerosis (MS)) with a combination of ADTC5 and BDNF significantly suppressed disease relapse compared to those treated with BDNF alone, ADTC5 alone, and PBS. 29 The results indicate that a combination of BDNF and ADTC5 peptide can be used to treat other brain neurodegenerative disease such as AD.…”

“…Previously, brain delivery of BDNF using ADTC5 in experimental autoimmune encephalomyelitis (EAE) induced oligodendrocyte maturation which was reflected in the increase in NG2 receptor expression in the brain. 29 Furthermore, BDNF +/+ mice have shown a significant upregulation of NG2 glia following the development of cuprizone-induced lesions compared to BDNF +/and BDNF -/mice. 43,44 Thus, the effects of BDNF brain delivery using ADTC5 were determined by evaluating the oligodendrocyte progenitor maturation in the APP/PS1 mouse model.…”