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Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

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Indomethacin restores LTM failure in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, indomethacin, a combined treatment of laminarin plus indomethacin (lamin + indo) or a combined treatment of laminarin plus NDGA (lamin + NDGA). None of the laminarin treated conditioned animals and laminarin + NDGA conditioned animals or any of the unconditioned animals responded with significant feeding movements upon amyl acetate application in the post-training test. Indomethacin only treated animals showed a significant increase in their Δrasp values compared to their unconditioned peers but this conditioned response was significantly smaller than observed in the vehicle conditioned animals. Both vehicle and laminarin + indomethacin treated conditioned animals responded with a significant increase in the Δrasp values compared to their unconditioned peers and the laminarin conditioned animals. This suggests that co-treatment of laminarin with a COX inhibitor reverses the laminarin induced adverse effect on LTM performance. ** = p < 0.01, *** p < 0.001, ns = not significant.
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Figure 7: Indomethacin restores LTM failure in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, indomethacin, a combined treatment of laminarin plus indomethacin (lamin + indo) or a combined treatment of laminarin plus NDGA (lamin + NDGA). None of the laminarin treated conditioned animals and laminarin + NDGA conditioned animals or any of the unconditioned animals responded with significant feeding movements upon amyl acetate application in the post-training test. Indomethacin only treated animals showed a significant increase in their Δrasp values compared to their unconditioned peers but this conditioned response was significantly smaller than observed in the vehicle conditioned animals. Both vehicle and laminarin + indomethacin treated conditioned animals responded with a significant increase in the Δrasp values compared to their unconditioned peers and the laminarin conditioned animals. This suggests that co-treatment of laminarin with a COX inhibitor reverses the laminarin induced adverse effect on LTM performance. ** = p < 0.01, *** p < 0.001, ns = not significant.

Mentions: Next, we tested the possibility of the involvement of the eicosanoid pathway in the laminarin-induced LTM impairment. For this purpose we used nordihydroguaiaretic acid (NDGA) and indomethacin, broad-spectrum inhibitors of, respectively, LOX and COX, the two major branches of the eicosanoid pathway. Drug administration, training and 24 hrs LTM assessment were performed according to procedures described before (Figure 7A). Consistent with previous results, laminarin-injected animals but not vehicle-injected animals failed to show robust conditioned feeding responses 24 hrs after their last training (Figure 7B, c.f., dotted bars and white bars; ANOVA treatment x training F4,222 = 3.02, p = 0.019, F1,222 = 23.522 p < 0.0001). The black bars in Figure 7B show that concurrent treatment with laminarin and NDGA (~10 μM haemolymph concentration) did not prevent LTM failure. In fact, the amyl-acetate evoked rasping response of conditioned animals pretreated with laminarin plus NDGA was indistinguishable from their unconditioned (CS-DS) counterparts (F1,222 = 0.028 p = 0.87). In contrast, the conditioned feeding response of indomethacin treated animals (~10 μM haemolymph concentration) differed significantly from that of their none conditioned counterparts (Figure 7B; contrast indo conditioned vs unconditioned F1,222 = 4.499, p = 0.04). However, as the figure illustrates the conditioned feeding response of indomethacin treated animals was significantly attenuated when compared with conditioned vehicle treated animals (Figure 7B; contrast vehicle vs Indo F1,222 = 6.166, p = 0.01). Interestingly, concurrent treatment with laminarin and indomethacin significantly improved conditioned feeding responses of the trained animals. That is, in contrast to the animals treated with laminarin only, animals that received laminarin plus indomethacin showed a robust conditioned feeding response (F1,222 = 7.911 p = 0.005) that was neither significantly different from the conditioned response of animals treated with vehicle-only (F1,222 = 3.018 p = 0.09) nor from that of animals treated with indomethacin only (F1,222 = 0.656 p = 0.42).


Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

Indomethacin restores LTM failure in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, indomethacin, a combined treatment of laminarin plus indomethacin (lamin + indo) or a combined treatment of laminarin plus NDGA (lamin + NDGA). None of the laminarin treated conditioned animals and laminarin + NDGA conditioned animals or any of the unconditioned animals responded with significant feeding movements upon amyl acetate application in the post-training test. Indomethacin only treated animals showed a significant increase in their Δrasp values compared to their unconditioned peers but this conditioned response was significantly smaller than observed in the vehicle conditioned animals. Both vehicle and laminarin + indomethacin treated conditioned animals responded with a significant increase in the Δrasp values compared to their unconditioned peers and the laminarin conditioned animals. This suggests that co-treatment of laminarin with a COX inhibitor reverses the laminarin induced adverse effect on LTM performance. ** = p < 0.01, *** p < 0.001, ns = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 7: Indomethacin restores LTM failure in laminarin treated animals. A. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B. LTM assessment in animals treated with either vehicle, laminarin, indomethacin, a combined treatment of laminarin plus indomethacin (lamin + indo) or a combined treatment of laminarin plus NDGA (lamin + NDGA). None of the laminarin treated conditioned animals and laminarin + NDGA conditioned animals or any of the unconditioned animals responded with significant feeding movements upon amyl acetate application in the post-training test. Indomethacin only treated animals showed a significant increase in their Δrasp values compared to their unconditioned peers but this conditioned response was significantly smaller than observed in the vehicle conditioned animals. Both vehicle and laminarin + indomethacin treated conditioned animals responded with a significant increase in the Δrasp values compared to their unconditioned peers and the laminarin conditioned animals. This suggests that co-treatment of laminarin with a COX inhibitor reverses the laminarin induced adverse effect on LTM performance. ** = p < 0.01, *** p < 0.001, ns = not significant.
Mentions: Next, we tested the possibility of the involvement of the eicosanoid pathway in the laminarin-induced LTM impairment. For this purpose we used nordihydroguaiaretic acid (NDGA) and indomethacin, broad-spectrum inhibitors of, respectively, LOX and COX, the two major branches of the eicosanoid pathway. Drug administration, training and 24 hrs LTM assessment were performed according to procedures described before (Figure 7A). Consistent with previous results, laminarin-injected animals but not vehicle-injected animals failed to show robust conditioned feeding responses 24 hrs after their last training (Figure 7B, c.f., dotted bars and white bars; ANOVA treatment x training F4,222 = 3.02, p = 0.019, F1,222 = 23.522 p < 0.0001). The black bars in Figure 7B show that concurrent treatment with laminarin and NDGA (~10 μM haemolymph concentration) did not prevent LTM failure. In fact, the amyl-acetate evoked rasping response of conditioned animals pretreated with laminarin plus NDGA was indistinguishable from their unconditioned (CS-DS) counterparts (F1,222 = 0.028 p = 0.87). In contrast, the conditioned feeding response of indomethacin treated animals (~10 μM haemolymph concentration) differed significantly from that of their none conditioned counterparts (Figure 7B; contrast indo conditioned vs unconditioned F1,222 = 4.499, p = 0.04). However, as the figure illustrates the conditioned feeding response of indomethacin treated animals was significantly attenuated when compared with conditioned vehicle treated animals (Figure 7B; contrast vehicle vs Indo F1,222 = 6.166, p = 0.01). Interestingly, concurrent treatment with laminarin and indomethacin significantly improved conditioned feeding responses of the trained animals. That is, in contrast to the animals treated with laminarin only, animals that received laminarin plus indomethacin showed a robust conditioned feeding response (F1,222 = 7.911 p = 0.005) that was neither significantly different from the conditioned response of animals treated with vehicle-only (F1,222 = 3.018 p = 0.09) nor from that of animals treated with indomethacin only (F1,222 = 0.656 p = 0.42).

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

Show MeSH
Related in: MedlinePlus