Study of cardiac autonomic function in drug-naive, newly diagnosed epilepsy patients

Background: Epilepsy is associated with ictal autonomic dysfunction which may extend into the inter-ictal period. Antiepileptic drugs have often been blamed for cardiac autonomic dysfunction in epilepsy patients. In this study we have investigated cardiac autonomic parameters in order to evaluate autonomic functions of drug-naive epilepsy patients. METHOD: Twenty drug-naive patients (15 males and 5 females) with epilepsy, and an equal number of age and gender matched controls, were evaluated for short-term resting heart rate variability and conventional cardiovascular autonomic measurements. Results: The mean age of patients was 29.30 +/- 9.80 yrs (17-55 yrs), mean age at seizure onset was 19.70 +/- 9.15 yrs (3-40 yrs) and mean length of time since last seizure was 5.60 +/- 7.00 days (1-30 days). While there was no difference in the resting heart rate or conventional autonomic test parameters, time domain heart rate variability measurements showed a decreased percentage of R-R intervals of less than 50 ms and root mean square of R-R intervals in patients, when compared to controls. Frequency domain parameters showed a decreased total power (patients: 1,796.58 +/- 1,052.45 ms2; controls: 2,934.23 +/- 1,767.06 ms2, p = 0.008). Parameters indicative of decreased vagal tone, i.e. decreased high frequency power and increased low to high frequency ratio (patients: 1.69 +/- 0.94; controls: 1.14 +/- 0.64, p = 0.045), were observed among patients compared to controls. CONCLUSION: Subtle but definite cardiac autonomic dysfunction, especially in vagal tone, was identified in drug-naive, new-onset epilepsy patients. Seizures can cause long-term and often progressive cardiac autonomic dysfunction which may be independent of concomitant antiepileptic drugs

Conditioned Medium Reconditions Hippocampal Neurons against Kainic Acid Induced Excitotoxicity: An In Vitro

Stem cell therapy is gaining attention as a promising treatment option for neurodegenerative diseases. The functional efficacy of grafted cells is a matter of debate and the recent consensus is that the cellular and functional recoveries might be due to “by-stander” effects of grafted cells. In the present study, we investigated the neuroprotective effect of conditioned medium (CM) derived from human embryonic kidney (HEK) cells in a kainic acid (KA) induced hippocampal degeneration model system in in vitro condition. Hippocampal cell line was exposed to KA (200 µM) for 24 hrs (lesion group) whereas, in the treatment group, hippocampal cell line was exposed to KA in combination with HEK-CM (KA + HEK-CM). We observed that KA exposure to cells resulted in significant neuronal loss. Interestingly, HEK-CM cotreatment completely attenuated the excitotoxic effects of KA. In HEK-CM cotreatment group, the cell viability was ~85–95% as opposed to 47% in KA alone group. Further investigation demonstrated that treatment with HEK-CM stimulated the endogenous cell survival factors like brain derived neurotrophic factors (BDNF) and antiapoptotic factor Bcl-2, revealing the possible mechanism of neuroprotection. Our results suggest that HEK-CM protects hippocampal neurons against excitotoxicity by stimulating the host’s endogenous cell survival mechanisms

Endosulfan induces small but significant changes in the levels of noradrenaline, dopamine and serotonin in the developing rat brain and deficits in the operant learning performance

The organochlorine insecticide, endosulfan was administered (6 mg/kg body weight) to Wistar rat pups of both sexes by gastric intubation daily from post-natal days 2-25. Its effect on levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) was assayed in olfactory bulb (OB), hippocampus (HI), visual cortex (VC), brainstem (BS) and cerebellum (CB) on days 10 and 25 using high-performanc liquid high-performance liquid chromatography (HPLC). The activity of acetylcholinesterase (AChE) was also estimated in the same regions of the brain. Performance in operant conditioning for solid food reward was assessed in 25-day-old rats. NA levels were increased in OB (12%, P < 0.01) and BS (10%, P < 0.05) at 10 days of age and in HI (20%, P < 0.01) and CB (12%, P < 0.05) at 25 days of age. DA level was decreased in HI at both 10 (42%, P < 0.001) and 25 (45%, P < 0.001) days. Serotonin levels were increased in OB (12%, P < 0.05), HI (41%, P < 0.001), VC (30%, P < 0.01) and BS (15%, P < 0.01) at 10 days of age but at 25 days, levels were decreased in BS (20%, P < 0.05) and CB (31%, P < 0.01). The activity of AChE was not different from the control groups in any of the regions studied. These data suggest that monoaminergic systems in the developing rat brain respond to endosulfan by undergoing something like a 'reorganization'. However, such changes do not ameliorate certain functional losses following the exposure to endosulfan as operant conditioning revealed deficits in acquisition as well as retention of memory

(−) Deprenyl attenuates Aluminium induced neurotoxicity in Primary cortical cultures

The role of (−) deprenyl in offering neuroprotection to cortical neurons exposed to Aluminium chloride (AlCl3) was examined. Primary cortical cultures derived from newborn rats were exposed to AlCl3on 6th day in vitro, at 100, 200, 400, 600, 800 and 1000 μM concentrations of AlCl3. After 48 h of AlCl3exposure, many nerve cell bodies were swollen; a beading of neurites and a disruption of the neuritic network were also observed suggesting neurodegeneration. Lactate dehydrogenase (LDH) efflux increased in a dose-dependent manner (59-120%). (−) Deprenyl co-exposure at concentrations of 10-7, 10-8 and 10-9M significantly attenuated both the morphological alterations and the LDH efflux induced by AlCl3. This in vitro study has demonstrated that (−) deprenyl can protect neurons from aluminium induced neurotoxicity

Mercuric chloride-induced alterations of levels of noradrenaline, dopamine, serotonin and acetylcholine esterase activity in different regions of rat brain during postnatal development

Wistar rats were fed mercuric chloride, 4 mg/kg body weight per day chronically from postnatal day 2 to 60 by gastric intubation. Mercury consumption was then discontinued until 170 days to allow time for recovery. Since mercury caused reduction in body weight, an underweight group was also included besides the normal saline group. Levels of noradrenaline (NA), dopamine (DA), 5-hydroxy-tryptamine (5-HT) and the activity of acetylcholine esterase (AChE) were assayed in various brain regions in different age groups. By 60 days of age, the mercury group showed elevations of NA levels in olfactory bulb (OB), visual cortex (VC) and brain stem (BS) but not in striatum-accumbens (SA) and hippocampus (HI). DA levels were also increased in OB, HI, VC and BS but not in SA. AChE activity was decreased in the mercury group only in HI and VC at 20 days of age. The Mercury group showed no behavioural abnormality outwardly; however, operant conditioning revealed a dificiency in performance. Nevertheless, all these changes disappeared after discontinuation of mercury intake. Thus the changes occurring in the brain at this level of oral mercuric chloride intake seem to reflect adaptive neural mechanisms rather than pathological damage

Levels of dopamine and noradrenaline in the developing retina - effect of light deprivation

The effect of light deprivation on the levels of dopamine and noradrenaline was studied in the developing rat retina. These transmitters were estimated in three groups of rats: (i) cycling light reared; (ii) dark reared since birth; and (iii) dark reared since birth, but exposed to cycling light for 1 day prior to the estimation of catecholamines. Our results show that (1) there is a progressive decrease in the levels of dopamine and noradrenaline in the cycling light and dark reared rats during postnatal development; (2) dark rearing further reduces the content of dopamine and noradrenaline; and (3) restoration of physiological (light) stimulus in the dark-reared rats during the early postnatal period results in the recovery of noradrenaline to a greater extent than that of dopamine. This study demonstrates a progressive decrease in the plasticity of dopaminergic system during retinal development, while such a decrease is not apparent in the noradrenergic system

Sporadic amyotrophic lateral sclerosis (SALS) – skeletal muscle response to cerebrospinal fluid from SALS patients in a rat model

Skeletal muscle atrophy is the most prominent feature of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease of motor neurons. However, the contribution of skeletal muscle to disease progression remains elusive. Our previous studies have shown that intrathecal injection of cerebrospinal fluid from sporadic ALS patients (ALS-CSF) induces several degenerative changes in motor neurons and glia of neonatal rats. Here, we describe various pathologic events in the rat extensor digitorum longus muscle following intrathecal injection of ALS-CSF. Adenosine triphosphatase staining and electron microscopic (EM) analysis revealed significant atrophy and grouping of type 2 fibres in ALS-CSF-injected rats. Profound neuromuscular junction (NMJ) damage, such as fragmentation accompanied by denervation, were revealed by α-bungarotoxin immunostaining. Altered expression of key NMJ proteins, rapsyn and calpain, was also observed by immunoblotting. In addition, EM analysis showed sarcolemmal folding, Z-line streaming, structural alterations of mitochondria and dilated sarcoplasmic reticulum. The expression of trophic factors was affected, with significant downregulation of vascular endothelial growth factor (VEGF), marginal reduction in insulin-like growth factor-1 (IGF-1), and upregulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). However, motor neurons might be unable to harness the enhanced levels of BDNF and GDNF, owing to impaired NMJs. We propose that ALS-CSF triggers motor neuronal degeneration, resulting in pathological changes in the skeletal muscle. Muscle damage further aggravates the motor neuronal pathology, because of the interdependency between them. This sets in a vicious cycle, leading to rapid and progressive loss of motor neurons, which could explain the relentless course of ALS. This article has an associated First Person interview with the first author of the paper