Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.
Postpartum depression (PPD) is a psychiatric disorder that occurs in 10-15% of childbearing women. It is hypothesized that omega-3 fatty acids, which are components of fish oil, may attenuate depression symptoms. In order to examine this hypothesis, the animal model of postpartum depression was established in the present study. Ovariectomized female rats underwent hormone-simulated pregnancy (HSP) regimen and received progesterone and estradiol benzoate or vehicle for 23 days, mimicking the actual rat's pregnancy. The days after hormone termination were considered as the postpartum period. Forced feeding of menhaden fish oil, as a source of omega-3, with three doses of 1, 3, and 9g/kg/d, fluoxetine 15mg/kg/d, and distilled water 2ml/d per rat started in five postpartum-induced and one vehicle group on postpartum day 1 and continued for 15 consecutive days. On postpartum day 15, all groups were tested in the forced swimming test (FST) and open field test (OFT), followed by a biochemical assay. Results showed that the postpartum-induced rats not treated with menhaden fish oil, exhibited an increase in immobility time seen in FST, hippocampal concentration of corticosterone and plasmatic level of corticosterone, and pro-inflammatory cytokines. These depression-related effects were attenuated by supplementation of menhaden fish oil with doses of 3 and 9g/kg. Moreover, results of rats supplemented with menhaden fish oil were comparable to rats treated with the clinically effective antidepressant, fluoxetine. Taken together, these results suggest that menhaden fish oil, rich in omega-3, exerts beneficial effect on postpartum depression and decreases the biomarkers related to depression such as corticosterone and pro-inflammatory cytokines.
Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.
Epilepsy is marked by seizures that are a manifestation of excessive brain activity and is symptomatically treatable by anti-epileptic drugs (AEDs). Unfortunately, the older AEDs have many side effects, with cognitive impairment being a major side effect that affects the daily lives of people with epilepsy. Thus, this study aimed to determine if newer AEDs (Zonisamide, Levetiracetam, Perampanel, Lamotrigine and Valproic Acid) also cause cognitive impairment, using a zebrafish model. Acute seizures were induced in zebrafish using pentylenetetrazol (PTZ) and cognitive function was assessed using the T-maze test of learning and memory. Neurotransmitter and gene expression levels related to epilepsy as well as learning and memory were also studied to provide a better understanding of the underlying processes. Ultimately, impaired cognitive function was seen in AED treated zebrafish, regardless of whether seizures were induced. A highly significant decrease in γ-Aminobutyric Acid (GABA) and glutamate levels was also discovered, although acetylcholine levels were more variable. The gene expression levels of Brain-Derived Neurotrophic Factor (BDNF), Neuropeptide Y (NPY) and Cyclic Adenosine Monophosphate (CAMP) Responsive Element Binding Protein 1 (CREB-1) were not found to be significantly different in AED treated zebrafish. Based on the experimental results, a decrease in brain glutamate levels due to AED treatment appears to be at least one of the major factors behind the observed cognitive impairment in the treated zebrafish.
In the present study, the effect α-asarone on nicotine withdrawal-induced depression-like behavior in mice was investigated. In this study, mice were exposed to drinking water or nicotine solution (10-200µg/ml) as a source of drinking for forty days. During this period, daily fluid consumption, food intake and body weight were recorded. The serum cotinine level was estimated before nicotine withdrawal. Naïve mice or nicotine-withdrawn mice were treated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) for eight consecutive days and the forced swim test (FST) or locomotor activity test was conducted. In addition, the effect of α-asarone or bupropion on the hippocampal pCREB, CREB and BDNF levels during nicotine-withdrawal were measured. Results indicated that α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment did not significantly alter the immobility time in the FST or spontaneous locomotor activity in naïve mice. However, the immobility time of nicotine-withdrawn mice was significantly attenuated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment in the FST. Besides, α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment significantly attenuated the hippocampal pCREB levels in nicotine-withdrawn mice. Overall, the present results indicate that α-asarone treatment attenuated the depression-like behavior through the modulation of hippocampal pCREB levels during nicotine-withdrawal in mice.
A single Leptospira strain (designated Bejo-Iso9(T)) was isolated from a soil sample taken in Johor, Malaysia. The isolate showed motility and morphology typical of the genus Leptospira under dark-field microscopy. Cells were found to be 10-13 microm in length and 0.2 microm in diameter, with a wavelength of 0.5 microm and an amplitude of approximately 0.2 microm. Phenotypically, strain Bejo-Iso9(T) grew in Ellinghausen-McCullough-Johnson-Harris medium at 13, 30 and 37 degrees C, and also in the presence of 8-azaguanine. Serologically, strain Bejo-Iso9(T) produced titres towards several members of the Tarassovi serogroup, but was found to be serologically unique by cross-agglutinin absorption test and thus represented a novel serovar. The proposed name for this serovar is Malaysia. Phylogenetic analysis of 16S rRNA gene sequences placed this novel strain within the radiation of the genus Leptospira, with sequence similarities within the range 90.4-99.5% with respect to recognized Leptospira species. DNA-DNA hybridization against the three most closely related Leptospira species was used to confirm the results of the 16S rRNA gene sequence analysis. The G+C content of the genome of strain Bejo-Iso9(T) was 36.2 mol%. On the basis of phenotypic, serological and phylogenetic data, strain Bejo-Iso9(T) represents a novel species of the genus Leptospira, for which the name Leptospira kmetyi sp. nov. is proposed. The type strain is Bejo-Iso9(T) (=WHO LT1101(T)=KIT Bejo-Iso9(T)).
In the present study, we investigated the anti-Parkinson's effect of vanillic acid (VA) (12 mg/kg, 25 mg/kg, 50 mg/kg p.o.) against rotenone (2 mg/kg s.c.) induced Parkinson's disease (PD) in rats. The continuous administration of rotenone for 35 days resulted in rigidity in muscles, catalepsy, and decrease in locomotor activity, body weight, and rearing behaviour along with the generation of oxidative stress in the brain (rise in the TBARS, and SAG level and reduced CAT, and GSH levels). Co-treatment of VA and levodopa-carbidopa (100 mg/kg + 25 mg/kg p.o.) lead to a significant (P