Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.
Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume c...
| Главные авторы: | , , , , , , , , |
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| Формат: | Статья |
| Язык: | English |
| Опубликовано: |
Public Library of Science (PLoS)
2014-01-01
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| Серии: | PLoS ONE |
| Online-ссылка: | http://europepmc.org/articles/PMC4028295?pdf=render |
| _version_ | 1831620098389966848 |
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| author | M Paola Castelli Camilla Madeddu Alberto Casti Angelo Casu Paola Casti Maria Scherma Liana Fattore Paola Fadda M Grazia Ennas |
| author_facet | M Paola Castelli Camilla Madeddu Alberto Casti Angelo Casu Paola Casti Maria Scherma Liana Fattore Paola Fadda M Grazia Ennas |
| author_sort | M Paola Castelli |
| collection | DOAJ |
| description | Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively. |
| first_indexed | 2024-12-18T21:06:46Z |
| format | Article |
| id | doaj.art-901b4ea22f4742a4b3a34f1fdb600fa0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-18T21:06:46Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-901b4ea22f4742a4b3a34f1fdb600fa02022-12-21T20:52:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9807910.1371/journal.pone.0098079Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.M Paola CastelliCamilla MadedduAlberto CastiAngelo CasuPaola CastiMaria SchermaLiana FattorePaola FaddaM Grazia EnnasMethamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively.http://europepmc.org/articles/PMC4028295?pdf=render |
| spellingShingle | M Paola Castelli Camilla Madeddu Alberto Casti Angelo Casu Paola Casti Maria Scherma Liana Fattore Paola Fadda M Grazia Ennas Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. PLoS ONE |
| title | Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. |
| title_full | Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. |
| title_fullStr | Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. |
| title_full_unstemmed | Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. |
| title_short | Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. |
| title_sort | δ9 tetrahydrocannabinol prevents methamphetamine induced neurotoxicity |
| url | http://europepmc.org/articles/PMC4028295?pdf=render |
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