Long-term valproate treatment increases brain neuropeptide Y expression and decreases seizure expression in a genetic rat model of absence epilepsy

The mechanisms by which valproate, one of the most widely prescribed anti-epileptic drugs, suppresses seizures have not been fully elucidated but may involve up-regulation of neuropeptide Y (NPY). We investigated the effects of valproate treatment in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) on brain NPY mRNA expression and seizure control. GAERS were administered either valproate (42 mg.kg(−1) hr(−1)) or saline continuously for 5 days. Electroencephalograms were recorded for 24 hrs on treatment days 1, 3 and 5 and the percentage of time spent in seizure activity was analysed. NPY mRNA expression was measured in different brain regions using qPCR. Valproate treatment suppressed seizures by 80% in GAERS (p<0.05) and increased NPY mRNA expression in the thalamus (p<0.05) compared to saline treatment. These results demonstrate that long-term valproate treatment results in an upregulation of thalamic expression of NPY implicating this as a potential contributor to the mechanism by which valproate suppresses absence seizures

Preclinical drug evaluation for combination therapy in acute stroke using systematic review, meta-analysis, and subsequent experimental testing

There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more &apos;realistic&apos; model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes; nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective

Rhythmic neuronal activity in S2 somatosensory and insular cortices contribute to the initiation of absence-related spike-and-wave discharges

International audiencePURPOSE: The origin of bilateral synchronous spike-and-wave discharges (SWDs) that underlie absence seizures has been widely debated. Studies in genetic rodent models suggest that SWDs originate from a restricted region in the somatosensory cortex. The properties of this initiation site remain unknown. Our goal was to characterize the interictal, preictal and ictal neuronal activity in the primary and secondary cortical regions (S1, S2) and in the adjacent insular cortex (IC) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). METHODS: We performed electroencephalography (EEG) recordings in combination with multisite local field potential (LFP) and single cell juxtacellular recordings, and cortical electrical stimulations, in freely moving rats and those under neurolept-anesthesia. KEY FINDINGS: The onset of the SWDs was preceded by 5-9 Hz field potential oscillations, which were detected earlier in S2 and IC than in S1. Sustained SWDs could be triggered by a 2-s train of 7-Hz electrical stimuli at a lower current intensity in S2 than in S1. In S2 and IC, subsets of neurons displayed rhythmic firing (5-9 Hz) in between seizures. S2 and IC layers V and VI neurons fired during the same time window, whereas in S1 layer VI, neurons fired before layer V neurons. Just before the spike component of each SW complex, short-lasting high-frequency oscillations consistently occurred in IC ∼20 msec before S1. SIGNIFICANCE: Our findings demonstrate that the S2/IC cortical areas are a critical component of the macro-network that is responsible for the generation of absence-related SWDs

Five days of valproate treatment suppresses seizures in GAERS.

<p>(A) Representative EEG trace from a GAERS rat showing the characteristic spike-and-wave discharge of an absence seizure. GAERS were given valproate (black bars n = 6; 42 mg.kg-1 hr-1) or saline (white bars n = 6) continuously for 5 days. 24 hour EEG data were collected and the percent of time spent in seizure activity (B), number of seizures per hour (C) and seizure duration (D) was quantified for each animal. A two-tailed Mann Whitney U test at each time point shows that the percentage of time spent in seizure activity (B) and the number of seizures per hour (C) was significantly reduced only after five days of treatment. Data shown as mean±SEM *p<0.05 valproate treatment compared to saline control.</p

NPY mRNA expression is increased in the thalamus of valproate treated GAERS.

<p>Representative coronal pictures of dissected tissue from SCx (A); Thal (B); Arc (C). (D) NPY mRNA expression (relative to 18S mRNA expression) was significantly increased in the thalamus of valproate treated GAERS (black bars n = 6) compared to saline treated GAERS (white bars n = 6). Data shown as mean±SEM. *p<0.05 compared to saline controls (two tailed Mann Whitney U test). Thal - thalamus; SCx - Somatosensory cortex; Arc -arcuate nucleus.</p

Valproate does not affect food intake in GAERS.

<p>Food intake in saline (white bars n = 6) and valproate (black bars n = 6) treated GAERS at baseline and over the 5 day treatment period. There was no significant difference in food intake between GAERS receiving valproate compared to GAERS receiving saline treatment on each day of treatment (p>0.05, two-tailed Mann Whitney U test). Data shown as mean±SEM.</p