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Sesquiterpene lactones as potential therapeutic agents against Naegleria fowleri
Iñigo Arberas-Jiménez1, Aitor Rizo-Liendo1, Nathália Nocchi2
1Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), Universidad de La Laguna (ULL), Avenida Astrofísico Francisco Sánchez s/n, 38203 La Laguna, Tenerife, Spain; Departamento de Obstetricia y Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad de La Laguna, Tenerife, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET), Spain.
Abstract:
Naegleria fowleri is the causative agent the primary amoebic meningoencephalitis (PAM), a fatal disease in more than the 90% of the reported cases that affects the central nervous system. The amoeba infects the nasal cavity of mostly children and young adults who report previous aquatic exposure in warm water sources. The rapid progression of the disease and the lack of effective and safety therapeutic options make the search of new anti-amoebic compounds an urgent issue. In this study, twelve sesquiterpene lactones isolated from the zoanthid Palythoa aff. clavata were tested against the trophozoite stage of Naegleria fowleri. Anhydroartemorin (2) and 1(10)Z,4E,14-acetoxy-costunolide (3) showed the best anti-amoeboid activity values with IC50 23.02 ± 1.26 and 28.34 ± 6.27, respectively. In addition, the mechanisms of programmed cell death induction of these two molecules were evaluated with positive results for both compounds. Finally, a structure-activity relationship was analyzed to reveal the dependence of reactivity and lipophilicity on the biological activity. The log P values of the compounds were calculated to postulate them as good candidates to cross the blood-brain barrier, a limiting factor in the development of new anti-Naegleria treatments. Therefore, the mentioned sesquiterpene lactones could be considered as potential PAM therapeutic options in the future.
Insights
Sesquiterpene lactones from Palythoa aff. clavata show promise against Naegleria fowleri, the cause of primary amoebic meningoencephalitis (PAM). Two compounds demonstrated significant anti-amoeboid activity and induced programmed cell death, suggesting potential new treatments for this fatal brain infection.
Area of Science:
- Marine Natural Products Chemistry
- Parasitology
- Neuroscience
Background:
- Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), a devastating and often fatal central nervous system infection.
- High mortality rates (>90%) and limited therapeutic options necessitate the urgent discovery of novel anti-Naegleria treatments.
- Aquatic exposure, particularly in warm waters, is a common risk factor, with infections predominantly affecting children and young adults.
Purpose of the Study:
- To evaluate the anti-amoeboid activity of sesquiterpene lactones isolated from Palythoa aff. clavata against Naegleria fowleri.
- To investigate the mechanism of cell death induced by active compounds.
- To analyze structure-activity relationships and assess the potential of these compounds to cross the blood-brain barrier.
Main Methods:
- Twelve sesquiterpene lactones were isolated from the zoanthid Palythoa aff. clavata.
- In vitro assays were performed to determine the anti-amoeboid activity (IC50 values) against Naegleria fowleri trophozoites.
- Programmed cell death induction mechanisms were evaluated for the most potent compounds.
- Lipophilicity (log P values) was calculated to predict blood-brain barrier penetration.
Main Results:
- Anhydroartemorin (2) and 1(10)Z,4E,14-acetoxy-costunolide (3) exhibited significant anti-amoeboid activity with IC50 values of 23.02 ± 1.26 and 28.34 ± 6.27, respectively.
- Both active compounds effectively induced programmed cell death in Naegleria fowleri.
- Calculated log P values suggest these sesquiterpene lactones possess favorable characteristics for crossing the blood-brain barrier.
Conclusions:
- Sesquiterpene lactones, specifically anhydroartemorin and 1(10)Z,4E,14-acetoxy-costunolide, show significant potential as therapeutic agents against Naegleria fowleri.
- These compounds induce programmed cell death and possess properties conducive to treating PAM, including potential blood-brain barrier penetration.
- Further research into these marine-derived compounds could lead to the development of effective treatments for primary amoebic meningoencephalitis.
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