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

BACKGROUND AND PURPOSE: Kratom 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 APPROACH: Here, 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 RESULTS: We 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 IMPLICATIONS: The 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.

Mitragynine inhibits hippocampus neuroplasticity and its molecular mechanism.

BACKGROUND: Mitragynine (MIT), the primary indole alkaloid of kratom (Mitragyna speciosa), has been associated with addictive and cognitive decline potentials. In acute studies, MIT decreases spatial memory and inhibits hippocampal synaptic transmission in long-term potentiation (LTP). This study investigated the impacts of 14-day MIT treatment on hippocampus synaptic transmission and its possible underlying mechanisms. METHODS: Under urethane anesthesia, field excitatory post-synaptic potentials (fEPSP) of the hippocampal CA1 region were recorded in the Sprague Dawley (SD) rats that received MIT (1, 5, and 10 mg/kg), morphine (MOR) 5 mg/kg, or vehicle (ip). The effects of the treatments on basal synaptic transmission, paired-pulse facilitation (PPF), and LTP were assessed in the CA1 region. Analysis of the brain's protein expression linked to neuroplasticity was then performed using a western blot. RESULTS: The baseline synaptic transmission's amplitude was drastically decreased by MIT at 5 and 10 mg/kg doses, although the PPF ratio before TBS remained unchanged, the PPF ratio after TBS was significantly reduced by MIT (10 mg/kg). Strong and persistent inhibition of LTP was generated in the CA1 region by MIT (5 and 10 mg/kg) doses; this effect was not seen in MIT (1 mg/kg) treated rats. In contrast to MIT (1 mg/kg), MIT (5 and 10 mg/kg) significantly raised the extracellular glutamate levels. After exposure to MIT, GluR-1 receptor expression remained unaltered. However, NMDAε2 receptor expression was markedly downregulated. The expression of pCaMKII, pERK, pCREB, BDNF, synaptophysin, PSD-95, Delta fosB, and CDK-5 was significantly downregulated in response to MIT (5 and 10 mg/kg) exposure, while MOR (5 mg/kg) significantly raised synaptophysin and Delta fosB expression. CONCLUSION: Findings from this work reveal that a smaller dose of MIT (1 mg/kg) poses no risk to hippocampal synaptic transmission. Alteration in neuroplasticity-associated proteins may be a molecular mechanism for MIT (5 and 10 mg/kg)-induced LTP disruption and cognitive impairments. Data from this work posit that MIT acted differently from MOR on neuroplasticity and its underlying mechanisms.

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

Mitragynine, an indole alkaloid from the plant Mitragyna speciosa (Kratom), has been reported to modify hippocampal synaptic transmission. However, the role of glutamatergic neurotransmission modulating synaptic plasticity in mitragynine-induced synaptic changes is still unknown. Here, we determined the role of AMPA- and NMDA glutamate receptors in mitragynine-induced synaptic plasticity in the hippocampus. Male Sprague Dawley rats received either vehicle or mitragynine (10 mg/kg), with or without the AMPA receptor antagonist, NBQX (3 mg/kg), or the NMDA receptor antagonist, MK-801 (0.2 mg/kg). Field excitatory postsynaptic potentials (fEPSP) during baseline, paired-pulse facilitation (PPF) and long-term potentiation (LTP) were recorded in-vivo in the hippocampal CA1 area of anaesthetised rats. Basal synaptic transmission and LTP were significantly impaired after mitragynine, NBQX, and MK-801 alone, without an effect on PPF. Combined effects suggest a weak functional AMPA- as well as NMDA receptor antagonist action of mitragynine.

Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective.

The aging population increases steadily because of a healthy lifestyle and medical advancements in healthcare. However, Alzheimer's disease (AD) is becoming more common and problematic among older adults. AD-related cases show an increasing trend annually, and the younger age population may also be at risk of developing this disorder. AD constitutes a primary form of dementia, an irreversible and progressive brain disorder that steadily damages cognitive functions and the ability to perform daily tasks. Later in life, AD leads to death as a result of the degeneration of specific brain areas. Currently, the cause of AD is poorly understood, and there is no safe and effective therapeutic agent to cure or slow down its progression. The condition is entirely preventable, and no study has yet demonstrated encouraging findings in terms of treatment. Identifying this disease's pathophysiology can help researchers develop safe and efficient therapeutic strategies to treat this ailment. This review outlines and discusses the pathophysiology that resulted in the development of AD including amyloid-ß plaques, tau neurofibrillary tangles, neuroinflammation, oxidative stress, cholinergic dysfunction, glutamate excitotoxicity, and changes in neurotrophins level may sound better based on the literature search from Scopus, PubMed, ScienceDirect, and Google Scholar. Potential therapeutic strategies are discussed to provide more insights into AD mechanisms by developing some possible pharmacological agents for its treatment.

Toxicological evaluation of aqueous leaf extract of Terminalia catappa linn (combretaceae) in pregnant rats.

Introduction: Terminalia catappa (T. catappa) leaves are used in the treatment of hypertension, diabetes, cough, jaundice, indigestion etc, while the bark is used to treat diarrhea, dysentery, abscesses etc. Due to the acceptance and increased use of medicinal plants in pregnancy, there is a need to evaluate their toxicological profiles in pregnancy for safe use. This study aims to evaluate the toxicological effects of aqueous leaf extract of T. catappa in pregnant rats. Methods: acute toxicity study was carried out using Organization of Economic Corporation Development (OECD) 423 guidelines. Seventy-five rats (50 females and 25 males) were used at the age of 2 weeks just after weaning. The male rats were separated from the female rats in different cages and allowed to mature for 10 weeks. Then the rats were allowed to mate. After mating, 20 female rats with viable spermatozoa counts were selected and divided into 4 groups of 5 rats each (n=5). The control group received distilled water while the treatment groups II, III, and IV were administered with aqueous leaf extract of T. catappa orally at graded doses of 100, 200, and 400 mg/kg respectively for 21 consecutive days. The daily food and water intake, and weight were recorded. On the 22th day, the rats were anesthetized by chloroform inhalation, and blood samples were collected for haematological and biochemical analysis. The maternal livers, kidneys, and hearts were collected and weighed, and histological studies were carried out. The fetuses were removed and examined. An isolated tissue experiment was carried out on the myometrium of the pregnant rat uterus. The isometric reading of the uterine contractions was recorded. Results: the oral LD50 was found to be ≤2000-5000 mg/kg. There was a significant (p<0.05) increase in the mean food intake at the 100, 200, and 400 mg/kg doses of the extract used on the 14th and 21st days when compared to the 7th day. The renal function test showed a significant (p<0.05) increase for chloride. The liver function test revealed that the extract at 100 mg/kg dose, significantly (p<0.05) increased only Alkaline Phosphatase (ALP) liver enzyme, while at 200 mg/kg dose, only AST liver enzyme was significantly (p<0.05) increased, while at 400 mg/kg dose, ALT, AST, ALP, and albumin increased significantly (p<0.05) when compared to the control group. There was a significant (p<0.05) decrease in the relative organ weight of the liver at 400 mg/kg dose of the extract. The liver histology showed moderate hepatic vacuolation and necrosis, while the histology of the kidney showed slight tubular necrosis. Conclusion: this study has shown that the aqueous leaf extract of T. catappa is relatively not safe in the pregnant rats. Although it is non-toxic to the fetus, it exhibited tocolytic effect by inhibiting uterine contractions, thus it should be used with caution during pregnancy, especially in the third trimester or during labor.

Real time monitoring of dopamine release evoked by mitragynine (Kratom): An insight through electrochemical sensor.

BACKGROUND: Mitragynine, the major indole alkaloid from Mitragyna speciosa has been reported previously to possess abuse liability. However, there are insufficient data suggesting the mechanism through which this pharmacological agent causes addiction. AIMS: In this study, we investigated the effects of mitragynine on dopamine (DA) level and dopamine transporter (DAT) expression from the rat's frontal cortex. METHODS: DA level was recorded in the brain samples of animals treated with acute or repeated exposure for 4 consecutive days with either vehicle or mitragynine (1 and 30 mg/kg) using electrochemical sensor. Animals were then decapitated and the brain regions were removed, snap-frozen in liquid nitrogen and immediately stored at -80 °C. DA level was quantified using Enzyme linked immunosorbent assay (ELISA) kits and DAT gene expression was determined using quantitative real time polymerase chain reaction (RT-qPCR). RESULTS/OUTCOME: Mitragynine (1 and 30 mg/kg) did not increase DA release following acute treatment, however, after repeated exposure at day 4, mitragynine significantly and dose dependently increased DA release in the frontal cortex. In this study, we also observed a significant increase in DAT mRNA expression at day 4 in group treated with mitragynine (30 mg/kg). CONCLUSION/INTERPRETATION: Data from this study indicates that mitragynine significantly increased DA release when administered repeatedly, increased in DAT mRNA expression with the highest tested dose (30 mg/kg). Therefore, the rewarding effects observed after mitragynine administration could be due to its ability to increase DA content in certain areas of the brain especially the frontal cortex.