K.R. Abbasova

Drug delivery to the brain using surfactant-coated poly(lactide-co-glycolide) nanoparticles: Influence of the formulation parameters

Poly(lactide-co-glycolide) (PLGA) nanoparticles coated with poloxamer 188 (Pluronic((R)) F-68) or polysorbate 80 (Tween((R)) 80) enable an efficient brain delivery of the drugs after intravenous injection. This ability was evidenced by two different pharmacological test systems employing as model drugs the anti-tumour antibiotic doxorubicin and the agonist of opioid receptors loperamide, which being P-gp substrates can cross the blood-brain barrier (BBB) only in pharmacologically insignificant amounts: binding of doxorubicin to the surfactant-coated PLGA nanoparticles, however, enabled a high anti-tumour effect against an intracranial 101/8 glioblastoma in rats, and the penetration of nanoparticle-bound loperamide into the brain was demonstrated by the induction of central analgesic effects in mice. Both pharmacological tests could demonstrate that therapeutic amounts of the drugs were delivered to the sites of action in the brain and showed the high efficiency of the surfactant-coated PLGA nanoparticles for brain delivery. The results of the study also demonstrated that the efficacy of brain delivery by nanoparticles not only is influenced by the coating surfactants but also by other formulation parameters such as core polymer, drug, and stabilizer.

Structural alterations in the rat brain and behavioral impairment after status epilepticus: An MRI study.

Temporal lobe epilepsy (TLE) is one of the most common neurologic disorders often associated with behavioral impairments and cognitive deficit. Lithium-pilocarpine model of seizures in rodents reproduces many features of human convulsive status epilepticus (SE) and subsequent TLE. In this study, we have investigated changes in the rat brain after lithium-pilocarpine SE using a high-field MRI system for small animals in early and chronic periods after SE. We have studied the relationship between T2 relaxation time measured in these periods and the development of behavioral exploratory response to novelty and habituation in the open field test. A significant increase in T2 in the hippocampus and associated structures was found 2 days after SE and practically resolved by day seven, while an increase in T2 in the parietal and prefrontal cortex appeared 30 days after SE. High T2 values in the parietal cortex and thalamus on day two after SE were associated with an increased mortality risk. A substantial variability in T2 relaxation time was observed in the hippocampus and amygdala 30 days after SE. Rats survived after SE showed locomotor hyperactivity and disruption of long-term habituation in the open field test carried out 5 weeks after the seizures. Interestingly, T2 in the amygdala 30 days after SE had a strong correlation with hyperactivity in the novel open field. Therefore, the amygdala damage may be an important factor in the development of hyperactivity in the chronic period after SE.

The role of perioral afferentation in the occurrenceof spike-wave discharges in the WAG/Rij modelof absence epilepsy.

According to the focal cortical theory of absence epilepsy, spike-and-wave discharges (SWDs) have a cortical focal origin in the perioral region of the somatosensory cortex in rats. In the present study the role of peripheral afferents of the perioral (snout) region in the occurrence of spontaneous SWDs was investigated in the WAG/Rij (Wistar Albino Glaxo from Rijswijk) rat model of absence epilepsy in order to examine whether an input from peripheral sources is imperative for the occurrence of SWDs. Twelve male WAG/Rij rats were chronically equipped with cortical EEG electrodes. Peripheral afferents of the perioral region of the snout nervus trigeminus were pharmacologically blocked with a local injection of 2% Novocain, a blockade of nervus facialis and saline injections were used as controls. ECoGs were recorded before and after bilateral injection of the drug. Blockade of the n. trigeminus decreased the incidence and duration of SWD, while similar injections with Novocain near the n. facialis had no effect. Injections with saline were also not effective. Our data demonstrate that intact peripheral afferent input may be primarily involved in the initiation of SWDs. It suggests that the cortico-thalamo-cortical circuits need the peripheral stimulations from the snout and vibrissae for an initiation of the spontaneous SWDs.

Fetal valproate syndrome as an experimental model of autism

High doses of valproic acid (VPA) can modify the activity of many genes by blocking histone deacetylases. Prenatal administration of VPA results in the development of fetal valproate syndrome in the offspring of laboratory animals. This syndrome is considered as a model of autism spectrum disorders. In this review, we discuss the characteristics of the brain state and activity during fetal valproate syndrome at different levels: from the molecular and cellular processes to the behavior. The characteristics of social interaction—the most relevant manifestations of autistic disorders—receive special attention. We present literature data and our own results.

Nanoparticle-based delivery of carbamazepine: A promising approach for the treatment of refractory epilepsy

Graphical abstract Figure. No caption available. ABSTRACT Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P‐glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid‐induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188‐coated PLGA nanoparticles enabled a 30‐fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.

Does status epilepticus modify the effect of ifenprodil on cortical epileptic afterdischarges in immature rats

BACKGROUND Ifenprodil as a specific antagonist of NMDA receptors containing a dominant NR2B subunit exhibits age-dependent anticonvulsant action. Possible changes of this action due to status epilepticus (SE) elicited at early stage of development were studied using cortical epileptic afterdischarges (ADs) as a model. METHODS Lithium-pilocarpine SE was induced at postnatal day 12 and effects of ifenprodil were studied 3, 6, 9, and 13 days after SE in rat pups with implanted epidural electrodes. Controls (LiPAR) received saline instead of pilocarpine. ADs were elicited by low frequency stimulation of sensorimotor cortex. Intensity of stimulation current increased in 18 steps from 0.2 to 15 mA. Ifenprodil (20 mg/kg) was administered intraperitoneally (ip) after the stimulation with 3.5-mA current. Threshold for four different phenomena as well as duration of ADs were evaluated. RESULTS The threshold for the transition into the limbic type of ADs was higher in 15-day-old SE rats than in LiPAR controls. Opposite difference was found in 18-day-old animals, older rats did not exhibit any difference. Isolated significant changes in total duration of ADs were found after high stimulation intensities. These changes appeared in 18-day-old rats where ADs were shorter in SE than in control LiPAR rats. CONCLUSIONS Changes in ifenprodil action were found only in the first week after SE but not in the second week. Interpretation of the results is complicated by failure of significant differences between SE and LiPAR rats probably due to a high dose of paraldehyde.

The role of blood-brain barrier in the development of childhood febrile seizures and temporal lobe epilepsy

The blood-brain barrier (BBB) of the central nervous system (CNS) is a physiological barrier that makes it possible to control the exchange of ions, molecules and cells between blood and brain tissue and prevent their free inflow into the brain. BBB is crucial for maintenance of brain homeostasis. The BBB damage accompanies many degenerative, neurological and inflammatory (infectious or noninfectious) diseases and pathological states. Current review reports about the BBB role in the development of childhood febrile seizures and temporal lobe epilepsy.