Neuroprotective effects of methyl jasmonate in male Wistar rats exposed to delayed acetic acid-induced ulcerative colitis: involvement of antioxidant status, GFAP, and IBA-1 immunoreactivities.

Neurobehavioral deficits have been severally reported as a comorbid outcome in inflammatory bowel diseases (IBDs). This study evaluated neurological changes in the experimental model of IBDs, as well potential protective effects of methyl jasmonate (MJ). The study used the acetic acid model of colitis and thereafter delayed the healing process by the administration of indomethacin (Indo) (2 mg/kg, SC). Thirty male Wistar rats (120-160 g) were divided into 5 groups (n = 6). Control, Colitis, Colitis + Indo, MJ (50 mg/kg, IP) + Colitis and MJ + Colitis + Indo. Colitis was induced by intrarectal administration of 2 mL, 4% acetic acid. Neurobehavioral studies were carried out to assess memory function, depression, and anxiety on day 7 of post-colitis induction. Animals were thereafter sacrificed to collect the brain tissues for routine histology, immunoreactivity of GFAP and IBA-1, and biochemical assays. Neurobehavioral tests showed anxiety, depression, and memory deficits, especially in the Colitis + Indo group which were accompanied by increased IBA-1 and GFAP count. MJ reversed these effects and reduced GFAP count in the hippocampus and amygdala as well as IBA-1 count in the hippocampus, amygdala, and cortex. Histological observations of these areas showed no significant histopathological changes across all groups. GPx and CAT levels were significantly reduced, while MPO was significantly increased in colitis and Colitis+indo groups when compared with control, which was attenuated in groups administered with MJ. These findings tuggest that MJ possesses neuroprotective, anti-oxidant, and neuron-regeneration properties. Therefore, it could be considered as a potential treatment for behavioral deficits associated with ulcerative colitis.

Nω-nitro-L-arginine, a nitric oxide synthase inhibitor, attenuates nickel-induced neurotoxicity.

The various mediums of exposure to nickel (Ni) compounds have raised enormous public health concerns, as it has been illustrated to exert toxic effects in biological organs, including the brain. We have previously implicated the involvement of elevated nitric oxide (NO) in Ni-induced oxidative stress in the brain. Hence, the present study investigated the ameliorative potential of Nω-nitro-L-arginine (L-NA), a NO synthase inhibitor, following Ni-induced neurotoxicity. Adult male rats were divided into four groups; control (normal saline), 10 mg/kg Ni chloride (NiCl2) only, 1 mg/kg L-NA, or 2 mg/kg L-NA co-administered with NiCl2. The administration was via daily intraperitoneal injections for three weeks. Neurobehavioural assessments performed thereafter ascertained short-term spatial memory and anxiety. Furthermore, histological evaluations of the cortex, hippocampus, and striatum were carried out using routine hematoxylin and eosin technique, while the phosphotungstic acid hematoxylin method was used to express the degree of astrogliosis. Biochemical analysis of NO levels was examined along with other oxidative stress markers (superoxide dismutase, catalase, glutathione, glutathione S transferase, glutathione peroxidase, myeloperoxidase, and lipid peroxidation). The results illustrated altered behavioral responses, a higher population of degenerating neurons, and astrocytes in the NiCl2 group. There was also an elevation in the NO level and a corresponding reduction in antioxidant activities. However, these debilitating changes were ameliorated in the L-NA treated groups. These results demonstrate an association between alterations in NO synthesis pathway and Ni neurotoxicity, which may render neuronal cells susceptible to damage by oxidative stress. This may yet be another mechanism and useful therapeutic marker in deciphering Ni-induced neurotoxicity.

Application of Fluorescence Microscopy and Behavioral Assays to Demonstrating Neuronal Connectomes and Neurotransmitter Systems in C. elegans.

The nematode Caenorhabditis elegans (C. elegans) is a prevailing model which is commonly utilized in a variety of biomedical research arenas, including neuroscience. Due to its transparency and simplicity, it is becoming a choice model organism for conducting imaging and behavioral assessment crucial to understanding the intricacies of the nervous system. Here, the methods required for neuronal characterization using fluorescent proteins and behavioral tasks are described. These are simplified protocols using fluorescent microscopy and behavioral assays to examine neuronal connections and associated neurotransmitter systems involved in normal physiology and aberrant pathology of the nervous system. Our aim is to make available to readers some streamlined and replicable procedures using C. elegans models as well as highlighting some of the limitations.

Perturbed MAPK signaling in ASD: Impact of metal neurotoxicity.

The mitogen-activated protein kinase (MAPK) pathways are intracellular signaling pathways necessary for regulating various physiological processes, including neurodevelopment. The developing brain is vulnerable to toxic substances, and metals, such as lead, mercury, nickel, manganese, and others, have been proven to induce disturbances in the MAPK signaling pathway. Since a well-regulated MAPK is necessary for normal neurodevelopment, perturbation of the MAPK pathway results in neurodevelopmental disorders, including autism spectrum disorder (ASD). ASD affects brain parts responsible for communication, cognition, social interaction, and other patterned behaviors. Several studies have addressed the role of metals in the etiopathogenesis of ASD. Here, we briefly review the MAPK signaling pathway and its role in neurodevelopment. Furthermore, we highlight the role of metal toxicity in the development of ASD and how perturbed MAPK signaling may result in ASD.

Vascular Dysfunction in the Brain; Implications for Heavy Metal Exposures.

Normal or diseased conditions that alter the brain's requirement for oxygen and nutrients via alterations to neurovascular coupling have an impact on the level of the neurovascular unit; comprising neuronal, glial and vascular components. The communications between the components of the neurovascular unit are precise and accurate for its functions; hence a minute disturbance can result in neurovascular dysfunction. Heavy metals such as cadmium, mercury, and lead have been identified to increase the vulnerability of the neurovascular unit to damage. This review examines the role of heavy metals in neurovascular dysfunctions and the possible mechanisms by which these metals act. Risk factors ranging from lifestyle, environment, genetics, infections, and physiologic ageing involved in neurological dysfunctions were highlighted, while stroke was discussed as the prevalent consequence of neurovascular dysfunctions. Furthermore, the role of these heavy metals in the pathogenesis of stroke consequently pinpoints the importance of understanding the mechanisms of neurovascular damage in a bid to curb the occurrence of neurovascular dysfunctions.

The aging brain: impact of heavy metal neurotoxicity.

The aging process is accompanied by critical changes in cellular and molecular functions, which upset the homeostatic balance in the central nervous system. Accumulation of metals renders the brain susceptible to neurotoxic insults by mechanisms such as mitochondrial dysfunction, neuronal calcium-ion dyshomeostasis, buildup of damaged molecules, compromised DNA repair, reduction in neurogenesis, and impaired energy metabolism. These hallmarks have been identified to be responsible for neuronal injuries, resulting in several neurological disorders. Various studies have shown solid associations between metal accumulation, abnormal protein expressions, and pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic lateral sclerosis. This review highlights metals (such as manganese, zinc, iron, copper, and nickel) for their accumulation, and consequences in the development of neurological disorders, in relation to the aging brain.

Role of purinergic signaling pathways in the adaptogenic-like activity of methyl jasmonate in rats exposed to unpredictable chronic mild stress.

Objectives Purinergic signaling pathway has been implicated in maladaptation of animals subjected to chronic stress. Previous studies have shown that methyl jasmonate (MJ) exhibited adaptogenic properties in mice exposed to unpredictable chronic mild stress (UCMS) via antioxidant and neuroprotective-related mechanisms. Methods This study evaluated the role of purinergic system in adaptogenic-like activity of MJ. Male Wistar rats were treated intraperitoneally with vehicle (10 mL/kg) or MJ (25, 50, or 100 mg/kg) 30 min prior exposure to UCMS. Thereafter, rats were assessed for swimming endurance in forced swim test (FST) and post-swimming motor coordination on beam walk test (BWT) apparatus. The rats' brains were processed for adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine deaminase, and arginase quantification. Hematological parameters, cholesterol, triglyceride, creatinine, and urea nitrogen were also determined. Results MJ prolonged swimming endurance time and reversed stress-induced post-swimming motor dysfunction. The altered hematological parameters induced by UCMS in rats were significantly (p<0.05) attenuated by MJ. MJ also reversed UCMS-induced alterations of total cholesterol, triglyceride, creatinine, and urea nitrogen levels. MJ averted UCMS-induced alterations in purinergic system by decreasing ATP and ADP hydrolysis, adenosine deaminase, and arginase activities in rats' brains. Conclusions Overall, these findings further suggest that MJ has adaptogenic-like activity in rats exposed to UCMS, which may be related to modulation of the purinergic signaling pathway.

Role of purinergic signaling pathways in the adaptogenic-like activity of methyl jasmonate in rats exposed to unpredictable chronic mild stress.

Objectives Purinergic signaling pathway has been implicated in maladaptation of animals subjected to chronic stress. Previous studies have shown that methyl jasmonate (MJ) exhibited adaptogenic properties in mice exposed to unpredictable chronic mild stress (UCMS) via antioxidant and neuroprotective-related mechanisms. Methods This study evaluated the role of purinergic system in adaptogenic-like activity of MJ. Male Wistar rats were treated intraperitoneally with vehicle (10 mL/kg) or MJ (25, 50, or 100 mg/kg) 30 min prior exposure to UCMS. Thereafter, rats were assessed for swimming endurance in forced swim test (FST) and post-swimming motor coordination on beam walk test (BWT) apparatus. The rats' brains were processed for adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine deaminase, and arginase quantification. Hematological parameters, cholesterol, triglyceride, creatinine, and urea nitrogen were also determined. Results MJ prolonged swimming endurance time and reversed stress-induced post-swimming motor dysfunction. The altered hematological parameters induced by UCMS in rats were significantly (p<0.05) attenuated by MJ. MJ also reversed UCMS-induced alterations of total cholesterol, triglyceride, creatinine, and urea nitrogen levels. MJ averted UCMS-induced alterations in purinergic system by decreasing ATP and ADP hydrolysis, adenosine deaminase, and arginase activities in rats' brains. Conclusions Overall, these findings further suggest that MJ has adaptogenic-like activity in rats exposed to UCMS, which may be related to modulation of the purinergic signaling pathway.

Methyl jasmonate reverses chronic stress-induced memory dysfunctions through modulation of monoaminergic neurotransmission, antioxidant defense system, and Nrf2 expressions.

Unpredictable chronic mild stress (UCMS) has been shown to cause memory loss via increased oxidative stress and deregulation of monoaminergic and cholinergic neurotransmissions. Although the benefits of methyl jasmonate (MJ), a well-known anti-stress plant hormone against chronic stress-induced psychopathologies, have been earlier reported, its effects on antioxidant defense molecules, monoaminergic transmitters, and nuclear factor erythroid 2-related factor 2 (Nrf2) immunopositive cells have not been extensively studied. The present study was designed to examine its effect on memory functions, antioxidant biomarkers, monoaminergic transmitters, and Nrf2 immunopositive cell expression in rats exposed to UCMS. Rats received an intraperitoneal injection of MJ (10, 25, and 50 mg/kg) 30 min before exposure to UCMS daily for 28 days. Memory function was assessed on day 29 using a modified elevated plus maze and novel object recognition tests. The antioxidant biomarkers, level of monoamines (serotonin, noradrenaline, and dopamine), and Nrf2 immunopositive cell expression were determined in the rat brain tissues. The activity of cholinesterase and monoamine oxidase enzymes was also determined. MJ attenuated memory deficits and elevated the brain levels of monoamines in UCMS rats. UCMS-induced increase of brain cholinesterase and monoamine oxidase activities was inhibited by MJ. Also, MJ attenuated UCMS-induced decrease in antioxidant enzymes (CAT, GPx, GST, and SOD) and thiol contents in the brains of rats. UCMS-induced increase in NO level and Nrf2 immunopositive cell expression in the rat's brain was attenuated by MJ. Taken together, these findings suggest that increasing antioxidant defense molecules and monoaminergic/cholinergic neurotransmitters and decreasing the Nrf2 immunopositive cell expressions may contribute to the memory-promoting effects of MJ in rats exposed to UCMS.

Role for calcium signaling in manganese neurotoxicity.

BACKGROUND: Calcium is an essential macronutrient that is involved in many cellular processes. Homeostatic control of intracellular levels of calcium ions [Ca2+] is vital to maintaining cellular structure and function. Several signaling molecules are involved in regulating Ca2+ levels in cells and perturbation of calcium signaling processes is implicated in several neurodegenerative and neurologic conditions. Manganese [Mn] is a metal which is essential for basic physiological functions. However, overexposure to Mn from environmental contamination and workplace hazards is a global concern. Mn overexposure leads to its accumulation in several human organs particularly the brain. Mn accumulation in the brain results in a manganism, a Parkinsonian-like syndrome. Additionally, Mn is a risk factor for several neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. Mn neurotoxicity also affects several neurotransmitter systems including dopaminergic, cholinergic and GABAergic. The mechanisms of Mn neurotoxicity are still being elucidated. AIM: The review will highlight a potential role for calcium signaling molecules in the mechanisms of Mn neurotoxicity. CONCLUSION: Ca2+ regulation influences the neurodegenerative process and there is possible role for perturbed calcium signaling in Mn neurotoxicity. Mechanisms implicated in Mn-induced neurodegeneration include oxidative stress, generation of free radicals, and apoptosis. These are influenced by mitochondrial integrity which can be dependent on intracellular Ca2+ homeostasis. Nevertheless, further elucidation of the direct effects of calcium signaling dysfunction and calcium-binding proteins activities in Mn neurotoxicity is required.

Probable mechanisms involved in the antipsychotic-like activity of methyl jasmonate in mice.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. The clinical efficacy of antipsychotic drugs has been compromised by adverse effects, relapse, and therapeutic failures, thus necessitating search for alternative agents. Methyl jasmonate (MJ) is a bioactive compound reported to have beneficial effects in various neurological disorders. This study was undertaken to investigate the antipsychotic-like effects of MJ in mice. Male Swiss mice were pretreated intraperitoneally with MJ (25-100 mg/kg) or vehicle (10 mL/kg) 60 min prior to bromocriptine (5 mg/kg) or acute injection of ketamine (10 mg/kg). Thereafter, each mouse was observed for stereotype behaviors for 2 min at 10, 15, 20, 30, and 45 min post-bromocriptine injection. Another set of mice received MJ (25-100 mg/kg) or vehicle (10 mL/kg) 60 min after chronic ketamine injection (20 mg/kg, i.p) once daily for 14 consecutive days. Afterwards, locomotor activity and memory function in this sequence were evaluated using open field and Y-maze tests. The levels of malondialdehyde (MDA) and glutathione (GSH) and activity of catalase and superoxide dismutase (SOD) in the brain were determined. MJ significantly inhibited stereotypy behavior induced by bromocriptine or acute ketamine injection, which suggest antipsychotic-like activity. It also attenuated hyper-locomotion and memory deficits induced by chronic injection of ketamine in mice. The increased oxidative stress as shown by the altered brain levels of MDA, GSH, and activity of antioxidant enzymes induced by chronic injection of ketamine was reduced by MJ. Taken together, these findings suggest that MJ demonstrated antipsychotic-like property via mechanism related to its antioxidant property and interference with dopaminergic neurotransmission.

Effects of Methyl Jasmonate on Acute Stress Responses in Mice Subjected to Forced Swim and Anoxic Tests.

Methyl jasmonate (MJ) is an anti-stress hormone released by plants in response to external stressors and aids adaptation to stress. In this study, we evaluated the anti-stress activity of MJ using the forced swim endurance test (FSET) and anoxic tolerance test in mice. Male Swiss mice were given MJ (25-100 mg/kg, i.p) 30 min before the FSET and anoxic test were carried out. The first occurrence of immobility, duration of immobility, time spent in active swimming, and latency to exhaustion were assessed in the FSET. The onset to anoxic convulsion was measured in the anoxic tolerance test. MJ significantly (p < 0.05) delayed the first occurrence of immobility and shortened the period of immobility, which indicates anti-stress property. MJ also increased the time spent in active swimming and prolonged the latency to exhaustion, which further suggests anti-stress activity. In addition, it also exhibited anti-stress property as evidenced by prolonged latency to first appearance of anoxic convulsions. The results of this study suggest that MJ demonstrated anti-stress activity and may be useful as an energizer in times of body weakness or exhaustion. Although more studies are necessary before concluding on how MJ exerts its anti-stress activity, the present data suggest an action similar to adaptogens in boosting energy and resilience in the face of stress.