The role of AMPA and NMDA receptors in mitragynine effects on hippocampal synaptic plasticity

Effendy, Mohamad Azmeer; Yunusa, Suleiman; Mat, Noorul Hamizah; Has, Ahmad Tarmizi Che; Müller, Christian P.; Hassan, Zurina

doi:10.1016/j.bbr.2022.114169

Cited by 8 publications

(5 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work, SAHA reversed the effects of MIT withdrawal on I/O, PPF, and LTP. These findings suggest that the negative epigenetic regulation may mitigate MIT's hippocampus‐related transmission deficit earlier reported (Effendy et al, 2023). It may also suggest that hippocampal plasticity deficits after MIT withdrawal may depend on the epigenetic effects and contribute to cognitive deficits.…”

Section: Discussionsupporting

confidence: 77%

See 1 more Smart Citation

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Yunusa,

Müller,

Hassan

2024

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and PurposeKratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction‐like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid‐like properties.Experimental ApproachHere, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal.Key ResultsWe found that withdrawal from 14‐day mitragynine (1–10 mg·kg−1·day−1) treatment caused dose‐dependent behavioural withdrawal signs resembling those of morphine (5 mg·kg−1·day−1) withdrawal. However, mitragynine (5 and 10 mg·kg−1·day−1) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long‐term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up‐regulates HDAC2 expression. Targeting the epigenetic adaptations with the HDAC inhibitor, SAHA, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input/output curves, paired‐pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal.Conclusion and ImplicationsThe data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom/mitragynine withdrawal and addiction.

show abstract

Section: Discussionsupporting

confidence: 77%

“…Acute MIT treatment was reported to suppress LTP in the contralateral CA1 hippocampal region in rats (Effendy et al, 2023; Hassan et al, 2019), which is a cellular basis for memory (Bliss et al, 2018). Here, we also reported a deficit of hippocampal plasticity after MIT withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Yunusa,

Müller,

Hassan

2024

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…We found that synapse-specific genes that are involved in signaling pathways such as synaptic vesicle endocytosis, vesicle fusion, synaptic plasticity, LTP, etc. [ 50 ] were upregulated after TG treatment (Fig. 7 d).…”

Section: Discussionmentioning

confidence: 89%

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

Aktar,

Ferdousi,

Kondo

et al. 2023

GeroScience

View full text Add to dashboard Cite

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.

show abstract

“…Mitragynine, the major compound of kratom, was found to activate the GABAB receptor in a mitragynine-induced conditioned place preference test in rats [109]. Mitragynine was also found to show a weak functional AMPA and NMDA receptor antagonist action [110]. However, the neuroendocrine hypothalamicpituitary-adrenal axis is overactive, as evidenced by the excess production of monoamine neurotransmitters including serotonin, noradrenaline, and dopamine.…”

Section: Neurological Effects Of Kratommentioning

confidence: 99%

A critical Review on the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds

Hossain,

Sultana,

Nuinoon

et al. 2023

Preprint

View full text Add to dashboard Cite

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of Kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from Krat-om, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at oth-er central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated gene’s upregulatory cascades leading to play a pivotal role in neuroprotective actions while its long-high dose is evident to cause the neuronal disorder. Additionally, the anti-inflammatory, antioxidative, antibac-terial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve the ambiguities about the neuronal effects of kratom to demonstrate its prospects as a therapeutic target for neurodisorders connecting with other pharmacologi-cal effects.

show abstract

The role of AMPA and NMDA receptors in mitragynine effects on hippocampal synaptic plasticity

Cited by 8 publications

References 41 publications

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

A critical Review on the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds

Contact Info

Product

Resources

About