Acute enhancing effect of a standardized extract of Centella asiatica (ECa 233) on synaptic plasticity: an investigation via hippocampal long-term potentiation.

CONTEXT: ECa 233 is the standardized extract of Centella asiatica (L.) Urban. (Apiaceae). It contains at least 85% of triterpenoid glycosides and yields neuroprotective and memory-enhancing effects. However, the exact molecules exerting the effects might be triterpenic acid metabolites reproduced through gut metabolism after orally ingesting C. asiatica, not triterpenoid glycosides. OBJECTIVE: This study demonstrates the effect of unmetabolized ECa 233 on hippocampal synaptic plasticity after directly perfusing ECa 233 over acute brain slices. MATERIALS AND METHODS: The brain slices obtained from 7-week-old male Wistar rats were randomly divided into 4 groups. We perfused either artificial cerebrospinal fluid (ACSF), 0.01% DMSO, 10 µg/mL ECa 233, or 100 µg/mL on brain slices, and measured the long-term potentiation (LTP) magnitude to determine the synaptic plasticity of hippocampal circuits in each group. RESULTS: The LTP magnitude of ACSF, DMSO, 10 ug/mL ECa 233, and 100 ug/mL ECa 233 groups increased from 100% to 181.26 ± 38.19%, 148.74 ± 5.40%, 273.71 ± 56.66%, 182.17 ± 18.61%, respectively. ECa 233 at the concentration of 10 µg/mL robustly and significantly enhanced hippocampal LTP magnitude. The data indicates an improvement of the hippocampal synaptic plasticity. DISCUSSION AND CONCLUSIONS: This study emphasizes the effectiveness of triterpenoid glycosides in ECa 233 on synaptic plasticity enhancement. Therefore, this study supported and complimented the known effects of C. asiatica extract on the enhancement of synaptic plasticity, and subsequently, learning and memory, suggesting that ECa 233 could be a promising memory enhancing agent.

Reversible short-term and delayed long-term cognitive impairment induced by chronic mild cerebral hypoperfusion in rats.

Chronic cerebral hypoperfusion induced by aging in combination with vascular disorder potentially contributes to the development of vascular dementia. This study aimed to investigate the age-related changes in spatial performances in chronic mild cerebral hypoperfusion induced by permanent right common carotid artery occlusion (rCCAO) in rats. Four-month-old male Sprague-Dawley rats (n = 20) were randomly assigned into sham and rCCAO groups. Spatial performances of young adult rats (age 4-8 months) were evaluated repeatedly by the radial arm water maze at 6 days, and 1, 2 and 4 months after surgery. The spatial performance was re-assessed by the Morris water maze when the rats were 18 months old. The present results revealed that the rCCAO rats developed progressive deficit in spatial learning and memory, starting from day 6 and significant deficit was found at 2 months after rCCAO (p < 0.05). However, the spatial performance of the rCCAO rats was recovered at 4 months after surgery. Testing of the cognitive flexibility of the aged rCCAO rats (18 months old), indicated that the learning flexibility of the aged rCCAO rats was significantly impaired. This deficit was found in parallel with pronounced white matter damage in the corpus callosum and internal capsule and significant cell death in the dorsal hippocampus. Our results suggested that vascular risk insult in young adult rats resulted in spatial learning deficit which could be completely compensated later on. However, such previous vascular risk could be exacerbated by advancing age and subsequently lead to a deficit in cognitive flexibility with white matter damage and significant neuronal death in the dorsal hippocampus.

Standardized Centella asiatica (ECa 233) extract decreased pain hypersensitivity development in a male mouse model of chronic inflammatory temporomandibular disorder.

Chronic inflammatory temporomandibular disorder (TMD) pain has a high prevalence, and available nonspecific treatments have adverse side effects. ECa 233, a standardized Centella asiatica extract, is highly anti-inflammatory and safe. We investigated its therapeutic effects by injecting complete Freund's adjuvant (CFA) into right temporomandibular joint of mice and administering either ibuprofen or ECa 233 (30, 100, and 300 mg/kg) for 28 days. Inflammatory and nociceptive markers, bone density, and pain hypersensitivity were examined. CFA decreased ipsilateral bone density, suggesting inflammation localization, which ipsilaterally caused immediate calcitonin gene-related peptide elevation in the trigeminal ganglia (TG) and trigeminal subnucleus caudalis (TNC), followed by late increase of NaV1.7 in TG and of p-CREB and activation of microglia in TNC. Contralaterally, only p-CREB and activated microglia in TNC showed delayed increase. Pain hypersensitivity, which developed early ipsilaterally, but late contralaterally, was reduced by ibuprofen and ECa 233 (30 or 100 mg/kg). However, ibuprofen and only 100-mg/kg ECa 233 effectively mitigated marker elevation. This suggests 30-mg/kg ECa 233 was antinociceptive, whereas 100-mg/kg ECa 233 was both anti-inflammatory and antinociceptive. ECa 233 may be alternatively and safely used for treating chronic inflammatory TMD pain, showing an inverted U-shaped dose-response relationship with maximal effect at 100 mg/kg.

Inverted U-shaped response of a standardized extract of Centella asiatica (ECa 233) on memory enhancement.

The herb Centella asiatica has long been considered a memory tonic. A recent review found no strong evidence for improvement of cognitive function, suggesting negative results were due to limitations in dose, standardization and product variation. We used a standardized extract of C. asiatica (ECa 233) to study behavioral, cellular and molecular effects on learning and memory enhancement. ECa 233 (10, 30, and 100 mg/kg) was given orally to normal rats twice a day for 30 days. We used the Morris water maze to test spatial learning and performed acute brain slice recording to measure changes of synaptic plasticity in the hippocampus, a core brain region for memory formation. Plasticity-related protein expressions (NR2A, NR2B, PSD-95, BDNF and TrkB) in hippocampus was also measured. Rats receiving 10 and 30 mg/kg doses showed significantly enhanced memory retention, and hippocampal long-term potentiation; however, only the 30 mg/kg dose showed increased plasticity-related proteins. There was an inverted U-shaped response of ECa 233 on memory enhancement; 30 mg/kg maximally enhanced memory retention with an increase of synaptic plasticity and plasticity-related proteins in hippocampus. Our data clearly support the beneficial effect on memory retention of a standardized extract of Centella asiatica within a specific therapeutic range.

Effect of Centella asiatica on pathophysiology of mild chronic cerebral hypoperfusion in rats.

OBJECTIVE: The present study investigated the effect of standardized Centella asiatica extract on cognition and hippocampal pathology of mild chronic cerebral hypoperfusion (CCH) that was induced by permanent right common carotid artery occlusion (RCO) in rats. MATERIALS AND METHODS: Sixty-four male Sprague-Dawley rats were randomly divided into four groups of Sham-veh, Sham-C. asiatica, RCO-veh and RCO-C. asiatica, which were further divided into short-term and long-term CCH induction. Oral treatments with 20 mg/kg C. asiatica initiated 24 hours and 12 months after CCH and continued for 14 consecutive days. According to the cognition and histopathological evaluation period, the experiment was divided into 2 sets of either 2 or 12 months of CCH. RESULTS: Results showed that 2-month CCH induced learning flexibility deficit associated with CA1 neuronal damage and internal capsule (IC) astroglia activation. Long-lasting (12 months) mild CCH induced spatial learning, memory and flexibility deficits associated with progressive dorsal hippocampal damage. Treatment with 20 mg/kg of C. asiatica improved learning flexibility deficit after 2 and 12 months of CCH. C. asiatica ameliorated neuronal damage in the dorsal hippocampus at 2 months of CCH when given 24 hours after CCH onset. Treatment with C. asiatica after 12 months of cerebral blood flow reduction improved memory and learning flexibility deficits and was associated with the dentate gyrus neuronal damage reduction. CONCLUSION: Our finding indicates the therapeutic potential of C. asiatica either when given immediately after ischemic insult or when administered one year after ischemic insult, in a CCH rat model.

Tiliacora triandra (Colebr.) Diels leaf extract enhances spatial learning and learning flexibility, and prevents dentate gyrus neuronal damage induced by cerebral ischemia/reperfusion injury in mice.

OBJECTIVE: The present study investigated the effects of a local Thai vegetable, Tiliacora triandra (Colebr.) Diels, also known as Yanang, against cerebral ischemia/reperfusion injury in mice. MATERIALS AND METHODS: Thirty male ICR mice were divided into three experimental groups of BLCCAO + 10% Tween 80, BLCCAO + T. triandra 300 mg/kg, and BLCCAO + T. triandra 600 mg/kg. Cerebral ischemia/reperfusion was induced by three minutes of bilateral common carotid artery occlusion (BLCCAO) followed by 18 days of reperfusion. Leaf extract was administered orally 24 hours after arterial occlusion and continued for 18 consecutive days. Cognitive abilities were evaluated using the Morris water maze. Histological analysis was conducted in the dorsal hippocampus subregions CA1, CA3, and DG and white matter regions (the corpus callosum, internal capsule, and optic tract) using 0.1 % cresyl violet and 0.1% Luxol fast blue staining. RESULTS: Results showed that T. triandra leaf extract at the doses of 300 and 600 mg/kg significantly enhanced spatial learning, and learning flexibility, and prevented neuronal death in the DG of mice following ischemia/reperfusion. CONCLUSION: T. triandra leaf extract enhanced spatial learning, and learning flexibility, and prevented DG neuronal death in a mice model of cerebral ischemia/reperfusion.

Bacopa monnieri extract enhances learning-dependent hippocampal long-term synaptic potentiation.

Bacopa monnieri has been used in Ayurvedic medicine as a memory enhancer for a long time; however, its direct effect on synaptic plasticity has not been investigated. To the best of our knowledge, this study is the first to report the effect of B. monnieri on long-term synaptic potentiation in acute hippocampal slices. Adult male Wistar rats were orally administered either sterile water or the ethanolic extract of B. monnieri for 60 days. The extracellular recording was performed to measure the field excitatory postsynaptic potential in the acute hippocampal slices of these rats. Our results showed that B. monnieri extract significantly increased long-term potentiation magnitude compared with the control group, whereas there was no change in basal synaptic transmission. The data support the beneficial mnemonic effect of B. monnieri, and suggest that this effect might be because of the increase of learning-associated synaptic machinery, resulting in the long-term potentiation enhancement and strengthening of hippocampal synapses, which plays a critical role in learning and memory formation.