ABSTRACT
Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.
Subject(s)
Anxiety/genetics , Anxiety/psychology , Behavior, Animal , Depression/genetics , Depression/psychology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/psychology , Multiple Sclerosis, Chronic Progressive/genetics , Multiple Sclerosis, Chronic Progressive/psychology , TRPA1 Cation Channel/genetics , Animals , Antioxidants/pharmacology , Female , Hindlimb Suspension , Hippocampus/drug effects , Hippocampus/metabolism , Inflammation Mediators/metabolism , Mice , Mice, Inbred C57BL , Oximes/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Sertraline/pharmacology , TRPA1 Cation Channel/antagonists & inhibitorsABSTRACT
Arachis hypogaea L. (peanut) leaf is traditionally used for the treatment of insomnia in Asia. However, studies describing the safety and toxicity profile for this plant preparation are limited. Thus, the goal of this study was to investigate the toxicity of peanut leaf hydroalcoholic extract (PLHE) repeated treatment. The extract was administered orally (100, 300 or 1000 mg/kg) in male and female Wistar rats for 28 days (OECD guideline 407). PLHE treatment did not cause mortality or weight variation in the animals. Also, there was no alteration on locomotor activity (open field test), motor coordination (rotarod test), or anxiety behaviour (elevated plus-maze test). Male rats had a reduction in relative liver weight (100 mg/kg) and an increase in total kidney weight (1000 mg/kg), but there was no change in biochemical and haematological parameters after PLHE treatment. Free extracellular double-stranded DNA (dsDNA) levels was also evaluated, but PLHE treatment did not increase this parameter in rat organs. Also, the dose of 1000 mg/kg of PLHE significantly increased the total thiols in the liver of females compared with the control animals. Thus, PLHE did not induce toxicity after repeated exposure for 28 days in rats.
Subject(s)
Arachis , Plant Extracts/toxicity , Administration, Oral , Alcohols/chemistry , Animals , Female , Male , Plant Leaves , Rats, Wistar , Solvents/chemistry , Toxicity Tests, SubacuteABSTRACT
Central neuropathic pain is the main symptom caused by spinal cord lesion in relapsing-remitting multiple sclerosis (RRMS), but its management is still not effective. The transient receptor potential ankyrin 1 (TRPA1) is a pain detecting ion channel involved in neuropathic pain development. Thus, the aim of our study was to evaluate the role of TRPA1 in central neuropathic nociception induced by relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mouse model. In this model, we observed the development of similar clinical conditions of RRMS in C57BL/6 female mice through RR-EAE using MOG35-55 antigen and Quil A adjuvant. At the thirty-fifth day post-induction, C57BL/6 female mice demonstrated alteration in the RR-EAE score without motor impairment, mechanical and cold allodynia. Also, significative changes in demyelinating (Mog and olig-1) and neuroinflammatory (Iba1, Gfap and Tnfa) markers were observed, but this model did not alter Trpa1 RNA expression levels in the spinal cord. The hydrogen peroxide and 4-hydroxynonenal levels (TRPA1 agonists) were increased in RR-EAE induced mice, as well as the NADPH oxidase activity. The intragastric treatment of RR-EAE induced mice with TRPA1 antagonists (HC-030031 and A-967079) and antioxidant (α-lipoic acid and apocynin) caused an antiallodynic effect. Moreover, the intrathecal administration of TRPA1 antisense oligonucleotide, HC-030031, α-lipoic acid, and apocynin transiently attenuated mechanical and cold allodynia. Thus, TRPA1 plays a key role in the induction of neuropathic pain in this model of RR-EAE and can be a possible target for investigating the development of pain in RRMS patients.
