Selegiline ameliorates depression-like behaviors in rodents and modulates hippocampal dopaminergic transmission and synaptic plasticity

Ishikawa, Tomoyoshi; Okano, Motoki; Minami, Anzu; Tsunekawa, Hiroko; Satoyoshi, Hiroshi; Tsukamoto, Youichi; Takahata, Kazue; Muraoka, Susumu

doi:10.1016/j.bbr.2018.10.032

Cited by 25 publications

(20 citation statements)

References 57 publications

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“…Finally, our data showed an increase of dopamine content in hippocampus and PFC in PEA‐treated mice, accompanying the reduction of memory deficit induced by HFD. These data are consistent with the recent report that the increased hippocampal dopamine can restore memory deficits and depressive‐like behaviour in mice by modulating neurotrophin levels and synaptic plasticity (Ishikawa et al, 2019).…”

Section: Discussionsupporting

confidence: 93%

Palmitoylethanolamide counteracts brain fog improving depressive‐like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis

Lama

Pirozzi

Annunziata

et al. 2020

British J Pharmacology

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Background and Purpose High‐fat diet (HFD)‐induced obesity is accompanied by metabolic and neurochemical changes that have been associated with depression. Recent studies indicate that palmitoylethanolamide (PEA) exerts metabolic effects and holds neuroprotective potential. However, studies on HFD exposure in mice which investigate the effects of PEA on monoamine system and synaptic plasticity are limited. Experimental Approach In C57Bl/6J male mice, obesity was established by HFD feeding for 12 weeks. Then, mice were treated with ultra‐micronized PEA (30 mg·kg−1 daily p.o.) or vehicle for 7 weeks along with HFD. Mice receiving chow diet and vehicle served as controls. Thereafter, depressive‐, anhedonic‐like behaviour and cognitive performance were measured. Monoamine analyses were performed on brain areas (nucleus accumbens, Nac; prefrontal cortex, PFC; hippocampus), and markers of synaptic plasticity and neurogenesis were evaluated in hippocampus. Key Results PEA limited depressive‐ and anhedonic‐like behaviour, and cognitive deficits induced by HFD. PEA induced an increase in 5‐HT levels in PFC, and a reduction of dopamine and 5‐HT turnover in Nac and PFC, respectively. Moreover, PEA increased dopamine levels in the hippocampus and PFC. At a molecular level, PEA restored brain‐derived neurotrophic factor signalling pathway in hippocampus and PFC, indicating an improvement of synaptic plasticity. In particular, PEA counteracted the reduction of glutamatergic synaptic density induced by HFD in the stratum radiatum of the CA1 of the hippocampus, where it also exhibited neurogenesis‐promoting abilities. Conclusion and Implications PEA may represent an adjuvant therapy to limit depressive‐like behaviours and memory deficit, affecting monoamine homeostasis, synaptic plasticity and neurogenesis. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc

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Section: Discussionsupporting

confidence: 93%

Palmitoylethanolamide counteracts brain fog improving depressive‐like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis

Lama

Pirozzi

Annunziata

et al. 2020

British J Pharmacology

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“…Selegiline at 10 mg/kg suppressed depression-like behavior in MPTP mice, but rasagiline did not, even at a dose of 3 mg/kg that exerts relatively selective MAO-B inhibition. These results indicate that the antidepressant-like effects of selegiline in MPTP mice are independent of its MAO inhibitory capacity, consistent with the results of previous studies using naïve mice (Shimazu et al, 2005; Amiri et al, 2016; Ishikawa et al, 2019). Moreover, an L -Dopa equivalent dose (equivalent to 100 mg L -Dopa) of selegiline is 10-fold higher than that of rasagiline in patients with PD (Tomlinson et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

“…The mechanisms underlying the antidepressant-like effects of selegiline and pramipexole in MPTP mice may be attributable to the restoration of LTP impairment in the hippocampus–mPFC pathway. In addition, our recent study demonstrated the ameliorating effect of selegiline on depression-like behavior in rodents subjected to the TST and the forced swim test, and its preventative effect on hippocampal CA1 LTP impairment induced by low-frequency stimulation in naïve rats (Ishikawa et al, 2019). Although there are several reports about the association of physical and functional changes in hippocampus, as a region for emotional perception, with depression severity of patients with PD (van Mierlo et al, 2015; Györfi et al, 2017; Gou et al, 2018), there have been no reports showing the relationship between hippocampal LTP impairment and depression-like behavior in PD animal models.…”

Section: Discussionmentioning

confidence: 99%

Selegiline Recovers Synaptic Plasticity in the Medial Prefrontal Cortex and Improves Corresponding Depression-Like Behavior in a Mouse Model of Parkinson’s Disease

Okano

Takahata

Sugimoto

et al. 2019

Front. Behav. Neurosci.

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In patients with Parkinson’s disease (PD), non-motor symptoms (NMS) including depression and anxiety are often recognized before motor symptoms develop. Monoamine oxidase (MAO)-B inhibitors are therapeutically effective for motor symptoms; however, their effects on NMS in PD are yet to be fully assessed. Here, we aimed to explore the antidepressant-like effects of propargyl MAO-B inhibitors, selegiline and rasagiline, in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model, and to elucidate the mechanisms underlying these effects. Four repeated intraperitoneal injections of MPTP at 17.5 mg/kg to C57BL/6 mice led to a partial reduction in the number of nigrostriatal tyrosine hydroxylase-positive neurons and to the extension of immobility time during the tail suspension test (TST), without any obvious induction of motor deficits. A single subcutaneous administration of selegiline at 10 mg/kg shortened the extended immobility time of MPTP mice in the TST, without any increase in motor activities, suggesting that selegiline exerts antidepressant-like effects. In this test, rasagiline did not produce antidepressant-like effects, although the inhibitory effect of 3 mg/kg rasagiline on brain MAO activity was comparable to that of 10 mg/kg selegiline. The shortened immobility time in the TST correlated with reduced cortical dopamine (DA) turnover rates in MPTP mice treated with selegiline, but not in MPTP mice treated with rasagiline. These results suggest that MAO inhibition does not entirely account for the antidepressant-like effects of selegiline. Administration of selegiline (10 mg/kg), but not rasagiline (1 mg/kg), to MPTP mice restored the impaired long-term potentiation induced by high-frequency stimulation in the medial prefrontal cortex (mPFC), and normalized the reduced phosphorylation of Ca 2+ /calmodulin-dependent protein kinase IIα, which is known to be involved in neuroplasticity, in the frontal cortex. In MPTP mice, the antiparkinsonian drug pramipexole (0.3 mg/kg), a DA D 2 and D 3 receptor agonist, that has been shown to be effective in treating depression in PD, ameliorated depression-like behavior and synaptic dysfunction in the mPFC. Taken together, the antidepressant-like effects of selegiline in MPTP mice are attributable to the restoration of impaired synaptic plasticity in the mPFC, suggesting its potential for treating depression in early PD.

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“…The hippocampus, which recently has been identified as one of the key brain areas associated with depression and other psychiatric disorders, shows dendritic synaptic impairment and severe damage after chronic stress exposure [18,19]. Chronic unpredictable mild stress (CUMS) serves as a means to generate an animal model which mimics the common stressors experienced in humans.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Depression is an inflammatory-related condition, with the progression in neuronal damage resulting in major depression disorder. Ginsenoside-Rg1, a sterol extract from the herb Panax ginseng, has been shown to exert neuroprotective effects upon neurodegeneration disorders. However, whether ginsenoside-Rg1 confers antidepressant-like effects on neuroinflammation as associated with depression, as well as the possible mechanism involved in these neuroprotective effects, is currently unclear. In the present report, we show that treatment with ginsenoside-Rg1 (40 mg/kg, i.p.) significantly ameliorated depressive-like behaviors as induced by chronic unpredictable mild stress (CUMS) in a rat model of depression. Moreover, these CUMS rats treated with ginsenoside-Rg1 showed reductions in the levels of the oxidative stress products and the activity in the antioxidant stress kinase. Furthermore, CUMS rats treated with ginsenoside-Rg1 showed ameliorated neuroinflammation and associated neuronal apoptosis along with a reduction in dendritic spine atrophy and display of depressive behaviors. Taken together, the results of this study suggest that ginsenoside-Rg1 produces antidepressant-like effects in CUMS-exposed rats; and one of the mechanisms for these antidepressant-like effects of ginsenoside-Rg1 appears to involve protection against oxidative stress and thus the neuronal deterioration resulting from inflammatory responses. These findings provide evidence for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related depression.

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Selegiline ameliorates depression-like behaviors in rodents and modulates hippocampal dopaminergic transmission and synaptic plasticity

Cited by 25 publications

References 57 publications

Palmitoylethanolamide counteracts brain fog improving depressive‐like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis

Palmitoylethanolamide counteracts brain fog improving depressive‐like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis

Selegiline Recovers Synaptic Plasticity in the Medial Prefrontal Cortex and Improves Corresponding Depression-Like Behavior in a Mouse Model of Parkinson’s Disease

Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats

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