RESUMO
Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases. Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine. Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms. Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.
Assuntos
Proteínas de Caenorhabditis elegans , Canabidiol , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Doença de Parkinson , Idoso , Animais , Humanos , Caenorhabditis elegans/metabolismo , alfa-Sinucleína/metabolismo , Animais Geneticamente Modificados , Canabidiol/farmacologia , Reserpina/toxicidade , Reserpina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Neurônios Dopaminérgicos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/metabolismo , Doenças Neurodegenerativas/metabolismo , Modelos Animais de Doenças , Receptores Acoplados a Proteínas G/metabolismoRESUMO
We investigated the effects of maternal hypothyroidism on forebrain dopaminergic, GABAergic, and serotonergic systems and related behavior in adult rat offspring. Experimental gestational hypothyroidism (EGH) was induced by administering 0.02% methimazole (MMI) to pregnant rats from gestational day 9 to delivery. Neurotransmitter-related protein and gene expression were evaluated in offspring forebrain at postnatal day (P) 120. Exploratory behavior, contextual fear conditioning, locomotion, and 30-day reserpine Parkinson induction were assessed from P75-P120. Protein and gene expression assessments of medial prefrontal cortex showed group differences in dopaminergic, GABAergic, and serotonergic receptors, catabolic enzymes, and transporters. Striatum of MMI offspring showed an isolated decrease in the dopaminergic enzyme, tyrosine hydroxylase. MMI exposure increased GABA and dopamine receptor expression in amygdala. MMI offspring also had decreased state anxiety and poor contextual fear conditioning. We found that baseline locomotion was not changed, but reserpine treatment significantly reduced locomotion only in MMI offspring. Our results indicated that restriction of maternal thyroid hormones reduced dopaminergic, GABAergic, and serotoninergic forebrain components in offspring. Tyrosine hydroxylase deficiency in the striatum may underlie enhanced reserpine induction of Parkinson-like movement in these same offspring. Deficits across different neurotransmitter systems in medial prefrontal cortex and amygdala may underlie decreased state anxiety-like behavior and reduced fear conditioning in offspring, but no changes in trait anxiety-like behavior occurred with maternal MMI exposure. These findings strongly support the hypothesis that adequate delivery of maternal thyroid hormones to the fetus is crucial to the development of the central nervous system critical for emotion and motor regulation.
Assuntos
Hipotireoidismo/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade , Transtornos de Ansiedade , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Feminino , Neurônios GABAérgicos/metabolismo , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Exposição Materna , Metimazol/efeitos adversos , Metimazol/farmacologia , Neurotransmissores , Transtornos Parkinsonianos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Wistar , Reserpina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Hormônios Tireóideos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
1. Reserpine produced a direct in vitro non-selective inhibitory effect on smooth muscle contraction of endometrium-free rat uterus. 2. Reserpine uptake into uterine muscle and its antagonistic effect on contraction had a similar time course. 3. Reserpine had a relaxing effect similar to that of trifluoperazine and different from that of verapamil or papaverine, and also failed to exert any inhibitory effect on 45Ca uptake rate. 4. Both reserpine and trifluoperazine but not verapamil inhibited the acetylcholine-induced contraction when present during the Ca-release from intracellular stores. 5. It is hypothesized that reserpine exerts its inhibitory action intracellularly on the activation of smooth muscle contraction by sarcoplasmic Ca2+.