Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures

Russo, Emilio; Chimirri, Serafina; Aiello, Rossana; Fazio, Salvatore De; Leo, Antonio; Rispoli, Vincenzo; Marra, Rosario; Labate, Angelo; Fazio, Pasquale De; Citraro, Rita; Sarro, Giovambattista De

doi:10.1016/j.yebeh.2013.05.002

Cited by 31 publications

(25 citation statements)

References 77 publications

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“…A,B), but not after 5 months suspension (data not shown), suggesting that such drugs have an anxiolytic effect, which is, however, not retained in this animal model. Furthermore, no differences between groups were noted in animal speed, supporting the absence of locomotor impairment, which might have influenced tests results …”

Section: Resultsmentioning

confidence: 73%

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Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

et al. 2014

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SUMMARYObjective: Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) exert cholesterol-independent pleiotropic effects that include antithrombotic, antiinflammatory, and antioxidative properties. Moreover, both in vitro and in vivo studies have shown neuroprotective, antiseizure, and antiexcitotoxic effects of statins, suggesting their potential role in the treatment of neurologic diseases. Only a few studies have investigated whether statins modulate absence seizure activity and epileptogenesis. Methods: We investigated the effects of atorvastatin (5 and 10 mg/kg/day), simvastatin (10 mg/kg/day), and pravastatin (10 and 30 mg/kg/day), given orally for 17 consecutive weeks (starting at 45 days of age), on the development of absence seizures (electroencephalography [EEG] recordings), depressive-like behavior (forced swimming test [FST]), and anxiety levels (open field test [OF]) in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij) rats at the age of 6 months (1 month after suspension). WAG/Rij rats are a genetic animal model of absence epilepsy, epileptogenesis, and mild-depression comorbidity. The effects of statins were also studied after acute intraperitoneal injection for 4 h after administration of various doses in 6-months-old rats. Plasma cholesterol levels were measured throughout drug treatment. Results: We found that early long-term statin treatment possesses antiepileptogenic properties, reduced immobility time in the FST, and reduced anxiety in the OF, whereas they were not effective against established absence seizures when acutely administered. The observed effects were not related to changes in plasma cholesterol levels, which remained unchanged during drug treatment. Significance: Our results suggest that statins administration might be a possible intervention and promising strategy for preventing the epileptogenesis and/or behavioral comorbidity.

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Section: Resultsmentioning

confidence: 73%

“…Furthermore, no differences between groups were noted in animal speed, supporting the absence of locomotor impairment, which might have influenced tests results. 30…”

Section: Effects Of Statins On Wag/rij Rat Behaviormentioning

confidence: 99%

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

et al. 2014

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“…Learning and memory functions were assessed using a spatial acquisition task in an MWM [36]. The apparatus consisted of a circular basin (diameter=180cm, height=50cm) filled with water (24±1°C) to a depth of 30cm, with a clear (invisible) escape platform (diameter=8cm) placed 1cm below the water surface.…”

Section: Morris Water Maze Testmentioning

confidence: 99%

Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects

Palleria

Leo

Andreozzi

et al. 2017

Behavioural Brain Research

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Diabetes has been identified as a risk factor for cognitive dysfunctions. Glucagone like peptide 1 (GLP-1) receptor agonists have neuroprotective effects in preclinical animal models. We evaluated the effects of GLP-1 receptor agonist, liraglutide (LIR), on cognitive decline associated with diabetes. Furthermore, we studied LIR effects against hippocampal neurodegeneration induced by streptozotocin (STZ), a well-validated animal model of diabetes and neurodegeneration associated with cognitive decline. Diabetes and/or cognitive decline were induced in Wistar rats by intraperitoneal or intracerebroventricular injection of STZ and then rats were treated with LIR (300μg/kg daily subcutaneously) for 6 weeks. Rats underwent behavioral tests: Morris water maze, passive avoidance, forced swimming (FST), open field, elevated plus maze, rotarod tests. Furthermore, LIR effects on hippocampal neurodegeneration and mTOR pathway (AKT, AMPK, ERK and p70S6K) were assessed. LIR improved learning and memory only in STZ-treated animals. Anxiolytic effects were observed in all LIR-treated groups but pro-depressant effects in CTRL rats were observed. At a cellular/molecular level, intracerebroventricular STZ induced hippocampal neurodegeneration accompanied by decreased phosphorylation of AMPK, AKT, ERK and p70S6K. LIR reduced hippocampal neuronal death and prevented the decreased phosphorylation of AKT and p70S6K; AMPK was hyper-phosphorylated in comparison to CTRL group, while LIR had no effects on ERK. LIR reduced animal endurance in the rotarod test and this effect might be also linked to a reduction in locomotor activity during only the last two minutes of the FST. LIR had protective effects on cognitive functions in addition to its effects on blood glucose levels. LIR effects in the brain also comprised anxiolytic and pro-depressant actions (although influenced by reduced endurance). Finally, LIR protected from diabetes-dependent hippocampal neurodegeneration likely through an effect on mTOR pathway.

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“…1 and 2 and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 experimental summary. When two tests were performed on the same animal, at least one day (range 1-3) was allowed as previously described [13,46,47]. Experiments were always performed between 09:00 and 11:00 a.m. in order to avoid possible circadian alteration of test results.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…The elevated plus maze (EPM) consists of two opposing open arms and two opposing closed arms of the same size (45 cm x 10 cm) with walls 10 cm high connected by a central platform (10 x 10 cm) and elevated 80 cm above the floor, as previously described [13,47]. Rats are positioned in the central platform facing a closed arm and the number of entries into, time spent on each arm and central platform are measured.…”

Section: Elevated Plus Mazementioning

confidence: 99%

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures

Cited by 31 publications

References 77 publications

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

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