A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones

David J. Koss, Kathleen P. Hindley, Kanola C. David, Ines Mancini, Graziano Guella, Kristina Sepčić, Tom Turk, Katja Rebolj, Gernot Riedel, Bettina Platt, Roderick H. Scott*

*Corresponding author for this work

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Abstract

Background: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. Results: Acute application of poly-APS (0.5 μg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 μg/ml) also produced Ca2+ transients in ∼41% of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 μg/ml and 5 μg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 μg/ ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. Conclusion: Poly-APS induced pore formation in hippocampal neurones andsuch pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported.

Original languageEnglish
Article number1
JournalBMC Pharmacology
Volume7
DOIs
Publication statusPublished - 1 Mar 2007

Fingerprint

Porifera
Salts
Neurons
Membranes
Polymers
Diphenylhexatriene
Surface Plasmon Resonance
Electrophysiology
Polymerization
Membrane Potentials
Action Potentials
Cations
Permeability
Hippocampus
poly-APS
Calcium

Keywords

  • Surface plasmon resonance
  • Hippocampal Neurone
  • Dorsal Root Ganglion Neurone
  • Synthetic Compound
  • Marine Sponge

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones. / Koss, David J.; Hindley, Kathleen P.; David, Kanola C.; Mancini, Ines; Guella, Graziano; Sepčić, Kristina; Turk, Tom; Rebolj, Katja; Riedel, Gernot; Platt, Bettina; Scott, Roderick H.

In: BMC Pharmacology, Vol. 7, 1, 01.03.2007.

Research output: Contribution to journalArticle

Koss, David J. ; Hindley, Kathleen P. ; David, Kanola C. ; Mancini, Ines ; Guella, Graziano ; Sepčić, Kristina ; Turk, Tom ; Rebolj, Katja ; Riedel, Gernot ; Platt, Bettina ; Scott, Roderick H. / A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones. In: BMC Pharmacology. 2007 ; Vol. 7.
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abstract = "Background: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. Results: Acute application of poly-APS (0.5 μg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 μg/ml) also produced Ca2+ transients in ∼41{\%} of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 μg/ml and 5 μg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 μg/ ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. Conclusion: Poly-APS induced pore formation in hippocampal neurones andsuch pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported.",
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author = "Koss, {David J.} and Hindley, {Kathleen P.} and David, {Kanola C.} and Ines Mancini and Graziano Guella and Kristina Sepčić and Tom Turk and Katja Rebolj and Gernot Riedel and Bettina Platt and Scott, {Roderick H.}",
note = "David Koss is supported by a grant from the Alzheimer's Research Trust (ART). Kanola David thanks the Fernado Fellowship for support. Kristina Sepčić and Roderick Scott thank the Slovene Research Agency and the British Council in Slovenia for a Partnership in Science Project.",
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T1 - A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones

AU - Koss, David J.

AU - Hindley, Kathleen P.

AU - David, Kanola C.

AU - Mancini, Ines

AU - Guella, Graziano

AU - Sepčić, Kristina

AU - Turk, Tom

AU - Rebolj, Katja

AU - Riedel, Gernot

AU - Platt, Bettina

AU - Scott, Roderick H.

N1 - David Koss is supported by a grant from the Alzheimer's Research Trust (ART). Kanola David thanks the Fernado Fellowship for support. Kristina Sepčić and Roderick Scott thank the Slovene Research Agency and the British Council in Slovenia for a Partnership in Science Project.

PY - 2007/3/1

Y1 - 2007/3/1

N2 - Background: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. Results: Acute application of poly-APS (0.5 μg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 μg/ml) also produced Ca2+ transients in ∼41% of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 μg/ml and 5 μg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 μg/ ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. Conclusion: Poly-APS induced pore formation in hippocampal neurones andsuch pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported.

AB - Background: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. Results: Acute application of poly-APS (0.5 μg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 μg/ml) also produced Ca2+ transients in ∼41% of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 μg/ml and 5 μg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 μg/ ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. Conclusion: Poly-APS induced pore formation in hippocampal neurones andsuch pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported.

KW - Surface plasmon resonance

KW - Hippocampal Neurone

KW - Dorsal Root Ganglion Neurone

KW - Synthetic Compound

KW - Marine Sponge

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