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. 2019 Dec 8;8(12):630.
doi: 10.3390/antiox8120630.

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Donald G Matthews  1 , Maya Caruso  1 , Charles F Murchison  1   2 , Jennifer Y Zhu  1 , Kirsten M Wright  1 , Christopher J Harris  1   3 , Nora E Gray  1 , Joseph F Quinn  1   3 , Amala Soumyanath  1
Affiliations

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Donald G Matthews et al. Antioxidants (Basel). .

Abstract

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ - 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

Keywords: 5XFAD; Alzheimer’s disease; Centella asiatica; NRF2; antioxidant; cognitive function; memory; mouse model; neuritic dystrophy; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CAW impact on object recall and contextual fear memory. (A,B) Novel object recognition testing after 3 weeks CAW treatment (A—2 h post-habituation, B—24 h post-habituation) (Combined dose response—2 h p < 0.001, 24 h p < 0.001, WT vs 5XFAD – 2 h p = 0.45, 24 h p = 0.36, Females vs Males—2 h p = 0.022, 24 h p = 0.16) (C) Conditioned fear response analysis after 4 weeks CAW treatment (Combined dose response—p < 0.001, WT vs 5XFAD—p < 0.001, Females vs Males—p = 0.011). Individual data points shown with group means and standard deviations. n values: (A/B/C) WT females 0 mg/kg/d n = 15/19/16, 200 mg/kg/d n = 21/21/15, 500 mg/kg/d n = 17/14/15, 1000 mg/kg/d n = 11/12/15; 5XFAD females 0 mg/kg/d n = 21/23/20, 200 mg/kg/d n = 14/14/14, 500 mg/kg/d n = 10/9/15, 1000 mg/kg/d n = 13/12/16; WT males 0 mg/kg/d n = 14/18/17, 200 mg/kg/d n = 16/17/12, 500 mg/kg/d n = 8/11/13, 1000 mg/kg/d n = 8/8/15; 5XFAD males 0 mg/kg/d n = 15/16/18, 200 mg/kg/d n = 15/19/19, 500 mg/kg/d n = 9/7/14, 1000 mg/kg/d n = 6/9/11.
Figure 2
Figure 2
Centella asiatica water extract (CAW) impact on markers of synaptic density in the hippocampus and prefrontal cortex. Quantitative PCR analysis of (A,C) pre-synaptic marker synaptophysin (Combined dose response—hippocampus p < 0.001, cortex p = 0.001; WT vs 5XFAD—hippocampus p = 0.81, cortex p = 0.75; Females vs. Males—hippocampus p = 0.016, cortex p = 0.004) and (B,D) post-synaptic marker Psd95 (Combined dose response—hippocampus p = 0.026, cortex p = 0.005; WT vs 5XFAD-hippocampus p = 0.17, cortex p = 0.18; Females vs. Males—hippocampus p < 0.001, cortex p = 0.19) in the (A,B) hippocampus and (C,D) frontal cortex of nine month old WT and 5XFAD male and female littermates. All groups are expressed relative to female WT untreated control. Individual data points shown with group means and standard deviations. n values: (A/B/C/D) WT females 0 mg/kg/d n = 13/13/8/8, 200 mg/kg/d n = 8/8/0/0, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/7/8; 5XFAD females 0 mg/kg/d n = 12/12/8/8, 200 mg/kg/d n = 9/9/0/0, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/8/8; WT males 0 mg/kg/d n = 14/14/8/8, 200 mg/kg/d n = 10/10/0/0, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/8/8; 5XFAD males 0 mg/kg/d n = 10/10/8/8, 200 mg/kg/d n = 8/8/0/0, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/8/8.
Figure 3
Figure 3
CAW impact on markers of oxidative stress in hippocampus. Quantitative PCR analysis of NRF2-regulated antioxidant genes in the hippocampus of nine month old WT and 5XFAD male and female littermates: (A) Nrf2 (Combined dose response p = 0.007; WT vs. 5XFAD p < 0.001; Females vs. Males p = 0.57) (B) Ho-1 (Combined dose response p < 0.001; WT vs. 5XFAD p < 0.001; Females vs Males p = 0.020) (C) Nqo1 (Combined dose response p < 0.001; WT vs. 5XFAD p = 0.064; Females vs. Males p = 0.85) (D) Gclc (Combined dose response p < 0.001; WT vs. 5XFAD p = 0.64; Females vs. Males p = 0.066) All groups are expressed relative to female WT untreated control. Due to the heavy skew, all expression levels were logged transformed to better conform to model assumptions of normality. Individual data points shown with group means and standard deviations. n values: (A/B/C/D) WT females 0 mg/kg/d n = 13/13/11/11, 200 mg/kg/d n = 8/8/8/8, 500 mg/kg/d n = 7/7/8/8, 1000 mg/kg/d n = 8/8/8/8; 5XFAD females 0 mg/kg/d n = 12/12/12/11, 200 mg/kg/d n = 9/9/9/9, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/8/8; WT males 0mg/kg/d n = 14/14/13/14, 200mg/kg/d n = 10/10/10/10, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/7/8/8; 5XFAD males 0 mg/kg/d n = 10/9/10/10, 200 mg/kg/d n = 8/8/8/8, 500 mg/kg/d n = 8/7/8/8, 1000 mg/kg/d n = 8/8/8/8.
Figure 4
Figure 4
CAW impact on markers of oxidative stress in prefrontal cortex. (A–D) Quantitative PCR analysis of NRF2-regulated antioxidant genes in the frontal cortex of nine month old WT and 5XFAD male and female littermates: (A) Nrf2 (Combined dose response p = 0.53, WT vs. 5XFAD p < 0.001, Females vs. Males p = 0.042) (B) Ho-1 (Combined dose response p = 0.32, WT vs. 5XFAD p < 0.001, Females vs. Males p = 0.073) (C) Nqo1 (Combined dose response p = 0.001, WT vs. 5XFAD p = 0.068, Females vs. Males p = 0.042) (D) Gclc (Combined dose response p = 0.43, WT vs. 5XFAD p = 0.20, Females vs. Males p = 0.46). All groups are expressed relative to female WT untreated control. Individual data points shown with group means and standard deviations. n values: (A/B/C/D) WT females 0 mg/kg/d n = 8/8/8/8, 500 mg/kg/d n = 8/7/8/8, 1000 mg/kg/d n = 8/8/8/7; 5XFAD females 0 mg/kg/d n = 8/8/8/8, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/8/8; WT males 0 mg/kg/d n = 7/7/7/8, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 7/7/8/8; 5XFAD males 0 mg/kg/d n = 8/8/8/8, 500 mg/kg/d n = 8/8/8/8, 1000 mg/kg/d n = 8/8/7/8.
Figure 5
Figure 5
CAW impact on 5XFAD plaque burden. Pan Aβ immunohistochemical analysis of number of particles and total plaque area within the (A,B) hippocampus (Number of Aβ particles p = 0.74, Total Aβ area p = 0.86), and (C,D) cortex (Number of Aβ particles p = 0.66, Total Aβ area p = 0.93) of 5XFAD male and female littermates. Individual data points shown with group means and standard deviations. (E) Images of pan Aβ-stained coronal sections of right hemisphere. Dashed line box of untreated 5XFAD Aβ IHC expanded to show staining of amyloid plaques. n values: (A/B/C/D) 5XFAD females 0 mg/kg/d n = 5/5/5/5, 500 mg/kg/d n = 5/5/5/5, 1000 mg/kg/d n = 5/5/6/6; 5XFAD males 0 mg/kg/d n = 7/7/7/7, 500 mg/kg/d n = 5/5/5/5, 1000 mg/kg/d n = 6/6/6/6.
Figure 6
Figure 6
CAW impact on Aβ-associated oxidative stress in the hippocampus and cortex of 5XFAD mice. SOD1 immunohistochemical analysis of number of particles and total area within the (A,B) hippocampus (Number of SOD1 particles p < 0.001, Total SOD1 area p = 0.38), and (C,D) cortex (Number of SOD1 particles p = 0.008, Total SOD1 area p = 0.042) of 5XFAD male and female littermates. Individual data points shown with group means and standard deviations. (E) Images of SOD1-stained coronal sections of right hemisphere. Dashed line box of untreated 5XFAD expanded to show SOD1 IHC staining presumed to be around amyloid plaques seen in Figure 5E. n values: (A/B/C/D) 5XFAD females 0 mg/kg/d n = 5/5/5/5, 500 mg/kg/d n = 5/5/5/5, 1000 mg/kg/d n = 5/5/5/5; 5XFAD males 0 mg/kg/d n = 6/6/6/6, 500 mg/kg/d n = 5/5/5/5, 1000 mg/kg/d n = 6/6/6/6.
Figure 7
Figure 7
Putative model for CAW antioxidative protection of 5XFAD neurons. CAW facilitates increased expression of NRF2-mediated ARE gene expression in the hippocampus to heighten antioxidant response to Aβ oxidative toxicity. CAW-mediated mitigation of increased ROS in neurons, results in reduced oxidative stress and, subsequently, plaque-associated SOD1, which correlates with reduced neuritic dystrophy, and ultimately prevents permanent synaptic damage and neuronal death.
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