Publication
Methylphenidate-induced alterations in astrocytes: A comprehensive characterization
| Summary: | Methylphenidate (MPH) is the first-line drug of choice for the treatment of attention deficit hyperactivity disorder (ADHD), a highly prevalent condition in children that may also persist into adulthood. ADHD diagnosis, which is only based on the clinical history of the patient, is rapidly increasing, along with MPH prescription. MPH non-medical use is also a common practice mainly among students with intent to improve their cognitive performance. This represents a critical problem, intensified by the fact that there is poor knowledge regarding the chronic and long-term effects of MPH treatment on the brain, both under ADHD and healthy conditions. In addition, the neurobiological effects of MPH have not yet been fully characterized, particularly in glial cells, such as astrocytes, that play essential roles in healthy and diseased brain. Thus, the present work aimed to characterize the direct effects of MPH on astrocytes, and also to investigate the impact of MPH chronic exposure in control and ADHD animal models, simulating MPH non-therapeutic and therapeutic use, respectively. To achieve these goals, primary cultures of rat cortical astrocytes and both Wistar-Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats treated with a clinically relevant dose of MPH were used as in vitro and animal models, respectively. The present study showed that direct MPH treatment did not induce astrogliosis, but promoted apoptotic cell death in a concentration-dependent manner. Moreover, MPH was able to induce reactive oxygen species (ROS) and nitric oxide (NO) intracellular production by astrocytes, as well as an increase of inducible nitric oxide synthase (iNOS) protein levels. In addition, the nuclear factor-κB (NF-κB) signaling pathway was activated by MPH. Regarding animal studies, SHR animals showed a tendency to an increment of glial fibrillary acidic protein (GFAP) and iNOS levels in the hippocampus comparing to control animals, suggesting that this ADHD model presents a basal inflammatory status. Curiously, MPH treatment led to a significant increase of both GFAP and iNOS protein levels in control animals, whereas in SHR rats there was a slight beneficial effect. Regarding lipid peroxidation, MPH treatment decreased such levels only in ADHD animals both in the prefrontal cortex (PFC) and hippocampus. Interestingly, the ADHD animal model presented, particularly in the hippocampus, a basal lower antioxidant capacity compared to control rats, which MPH treatment tended to increase. Still in the hippocampus, MPH chronic treatment decreased the antioxidant capacity of controls (WKY-rats). In conclusion, MPH induced a moderate direct effect in astrocytes particularly related with oxidative and nitrosative stress. Nevertheless, in a more complex context using animal studies, the observed responses related to astrogliosis, oxidative/nitrosative stress and antioxidant capacity, demonstrate that MPH non-therapeutic use has detrimental outcomes, while MPH therapeutic use is beneficial under ADHD conditions.This work unveils for the first time some of the direct effects of MPH on astrocytes, and improved our knowledge about the central effects of both therapeutic and misuse of MPH. |
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| Main Authors: | Muga, Mariana Carvalho |
| Subject: | Metilfenidato Astrócitos Stress oxidativo/nitrosativo PHDA Hipocampo Methylphenidate Astrocytes Oxidative/Nitrosative stress ADHD Hippocampus |
| Year: | 2020 |
| Country: | Portugal |
| Document type: | master thesis |
| Access type: | embargoed access |
| Associated institution: | Universidade de Coimbra |
| Language: | English |
| Origin: | Estudo Geral - Universidade de Coimbra |
| Summary: | Methylphenidate (MPH) is the first-line drug of choice for the treatment of attention deficit hyperactivity disorder (ADHD), a highly prevalent condition in children that may also persist into adulthood. ADHD diagnosis, which is only based on the clinical history of the patient, is rapidly increasing, along with MPH prescription. MPH non-medical use is also a common practice mainly among students with intent to improve their cognitive performance. This represents a critical problem, intensified by the fact that there is poor knowledge regarding the chronic and long-term effects of MPH treatment on the brain, both under ADHD and healthy conditions. In addition, the neurobiological effects of MPH have not yet been fully characterized, particularly in glial cells, such as astrocytes, that play essential roles in healthy and diseased brain. Thus, the present work aimed to characterize the direct effects of MPH on astrocytes, and also to investigate the impact of MPH chronic exposure in control and ADHD animal models, simulating MPH non-therapeutic and therapeutic use, respectively. To achieve these goals, primary cultures of rat cortical astrocytes and both Wistar-Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats treated with a clinically relevant dose of MPH were used as in vitro and animal models, respectively. The present study showed that direct MPH treatment did not induce astrogliosis, but promoted apoptotic cell death in a concentration-dependent manner. Moreover, MPH was able to induce reactive oxygen species (ROS) and nitric oxide (NO) intracellular production by astrocytes, as well as an increase of inducible nitric oxide synthase (iNOS) protein levels. In addition, the nuclear factor-κB (NF-κB) signaling pathway was activated by MPH. Regarding animal studies, SHR animals showed a tendency to an increment of glial fibrillary acidic protein (GFAP) and iNOS levels in the hippocampus comparing to control animals, suggesting that this ADHD model presents a basal inflammatory status. Curiously, MPH treatment led to a significant increase of both GFAP and iNOS protein levels in control animals, whereas in SHR rats there was a slight beneficial effect. Regarding lipid peroxidation, MPH treatment decreased such levels only in ADHD animals both in the prefrontal cortex (PFC) and hippocampus. Interestingly, the ADHD animal model presented, particularly in the hippocampus, a basal lower antioxidant capacity compared to control rats, which MPH treatment tended to increase. Still in the hippocampus, MPH chronic treatment decreased the antioxidant capacity of controls (WKY-rats). In conclusion, MPH induced a moderate direct effect in astrocytes particularly related with oxidative and nitrosative stress. Nevertheless, in a more complex context using animal studies, the observed responses related to astrogliosis, oxidative/nitrosative stress and antioxidant capacity, demonstrate that MPH non-therapeutic use has detrimental outcomes, while MPH therapeutic use is beneficial under ADHD conditions.This work unveils for the first time some of the direct effects of MPH on astrocytes, and improved our knowledge about the central effects of both therapeutic and misuse of MPH. |
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