A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

Megill, Andrea; Lee, Taehee; DiBattista, Amanda M.; Song, Jung Min; Spitzer, Matthew H.; Rubinshtein, Mark; Habib, Lila K.; Capule, Christina C.; Mayer, Michael; Turner, R. Scott; Kirkwood, Alfredo; Yang, Jerry; Pak, Daniel T.S.; Lee, Hey Kyoung; Hoe, Hyang Sook

doi:10.1523/jneurosci.1615-12.2013

Cited by 22 publications

(57 citation statements)

References 37 publications

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“…7, A and B). Previous studies showed that shRNA knockdown of RasGRF1 in primary neurons completely blocked the effect of BTA-EG 4 on spine density increases (18), further supporting that Ras signaling is essential for the spinogenic activity of the BAM agents.…”

Section: Discussionmentioning

confidence: 65%

“…Previous work has reported that BTA-EG 4 and BTA-EG 6 could promote spine density increases in vitro in murine primary hippocampal neurons (37) and BTA-EG 4 could promote spine density increases in vivo in the hippocampus of wt mice and a 3ϫ tg mouse model for AD (18,19). The increase in spine density in neurons by BTA-EG 4,6 correlated with an increase in expression of RasGRF1 compared with control cells (37).…”

Section: Design and Evaluation Of Benzothiazole Amphiphiles (Bams) 1-mentioning

confidence: 84%

“…We previously reported the design, synthesis, and evaluation of two oligo(ethylene glycol) derivatives of benzothiazole aniline (BTA), BTA-EG 6 and BTA-EG 4 , which exhibited a variety of advantageous properties for the potential treatment of neurodegenerative diseases such as AD (17)(18)(19). Interestingly, BTA-EG 4 showed the capability to improve memory and learning in cognitive performance tests in both wild-type mice and in a mouse model for AD (18,19).…”

mentioning

confidence: 99%

“…Interestingly, BTA-EG 4 showed the capability to improve memory and learning in cognitive performance tests in both wild-type mice and in a mouse model for AD (18,19). This in vivo activity of BTA-EG 4 was also accompanied by a phenotypic increase in dendritic spine density (18,19). Because of the scarcity of small molecules known to increase dendritic spine density, this rare feature of benzothiazole amphiphiles is of particular interest and could be utilized as a tool to help study the relationship between spines and cognitive function.…”

mentioning

confidence: 99%

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Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Cifelli

Dozier

Chung

et al. 2016

Journal of Biological Chemistry

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The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Herein, we report the design and evaluation of a new class of benzothiazole amphiphiles that exhibit a dosedependent response leading to an increase in dendritic spine density in primary hippocampal neurons. Cell exposure studies reveal that the increase in spine density can persist for days in the presence of these compounds, but returns to normal spine density levels within 24 h when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity. Time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Biochemical studies support that promotion of spine formation by these compounds is accompanied by Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism for dendritic spine loss induced by Alzheimer-related aggregated amyloid-␤ peptides in primary neurons. Evaluation of this new group of spinogenic agents reveals that they also exhibit relatively low toxicity at concentrations displaying activity. Collectively, these results suggest that small molecules that promote spine formation could be potentially useful for ameliorating cognitive deficiencies associated with spine loss in neurodegenerative diseases such as Alzheimer disease, and may also find use as general cognitive enhancers.

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Section: Discussionmentioning

confidence: 65%

Section: Design and Evaluation Of Benzothiazole Amphiphiles (Bams) 1-mentioning

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Cifelli

Dozier

Chung

et al. 2016

Journal of Biological Chemistry

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“…For example, benzothiazole aniline (BTA) is a known amyloid-binding compound and has been shown to prevent beta-amyloid protein aggregations. 116 It also inhibits semen-derived enhancer of virus infection, which increases the infectiousness of HIV. Polyacrylate-based nanoparticles functionalized with BTA were used to impede semen-derived enhancer of virus infection mediation in HIV-infected cells.…”

Section: Targetingmentioning

confidence: 99%

Natural product-based nanomedicine: recent advances and issues

Watkins¹,

Wu²,

Zhang³

et al. 2015

IJN

150

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Natural products have been used in medicine for many years. Many top-selling pharmaceuticals are natural compounds or their derivatives. These plant- or microorganism-derived compounds have shown potential as therapeutic agents against cancer, microbial infection, inflammation, and other disease conditions. However, their success in clinical trials has been less impressive, partly due to the compounds’ low bioavailability. The incorporation of nanoparticles into a delivery system for natural products would be a major advance in the efforts to increase their therapeutic effects. Recently, advances have been made showing that nanoparticles can significantly increase the bioavailability of natural products both in vitro and in vivo. Nanotechnology has demonstrated its capability to manipulate particles in order to target specific areas of the body and control the release of drugs. Although there are many benefits to applying nanotechnology for better delivery of natural products, it is not without issues. Drug targeting remains a challenge and potential nanoparticle toxicity needs to be further investigated, especially if these systems are to be used to treat chronic human diseases. This review aims to summarize recent progress in several key areas relevant to natural products in nanoparticle delivery systems for biomedical applications.

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Benzothiazole amphiphiles promote RasGRF1‐associated dendritic spine formation in human stem cell‐derived neurons

2020

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Synaptic dysfunction has been implicated as an early cause of cognitive decline in neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD). Methods to slow down or reverse the loss of functional synapses, therefore, represent a promising avenue to explore for treating NDDs. We have previously reported the development of a class of benzothiazole amphiphiles (BAMs) that exhibited the capability to improve memory and learning both in wild‐type mice and in an AD rodent model, putatively through promoting RasGRF1‐associated formation of dendritic spines in hippocampal neurons. While these results represent a good first step in exploring a new approach to treating NDDs, the capability of these compounds to increase spine density has not been previously examined in a human neuronal model. Here, we found that neurons derived from differentiated human induced pluripotent stem cells exhibited both an increase in RasGRF1 expression and a phenotypic increase in the density of postsynaptic density protein 95‐positive puncta (which we use to provide an estimate of dendritic spine density) in BAM‐treated vs. control neurons. These results demonstrate that the previously observed spinogenic effects of BAMs in rodent neurons can be recapitulated in a human neuronal model, which further supports the potential utility of BAM agents for treating human diseases associated with spine deficits such as AD or other NDDs.

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A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

Cited by 22 publications

References 37 publications

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Natural product-based nanomedicine: recent advances and issues

Benzothiazole amphiphiles promote RasGRF1‐associated dendritic spine formation in human stem cell‐derived neurons

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