Saleh Al Deeb

Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents

Recent studies provide evidence that phospholipase A2 (PLA2) may play a role in the development of experimental parkinsonism. In this investigation an attempt was made to determine a possible protective effect of quinacrine (QNC), a PLA2 inhibitor on MPTP as well as 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in rodents. For MPTP studies, adult male mice (C57 BL) were treated with MPTP (30 mg/kg, i.p.) daily for 5 days. QNC was injected i.p. in the doses of 0, 10, 30 and 60 mg/kg daily 30 min before MPTP in four different groups. Two other groups of mice received either vehicle (control) or a high dose of QNC (60 mg/kg). Two hours after the last injection of MPTP, striata were collected for the analysis of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and glutathione (GSH). For the 6-OHDA study, male Wistar rats were infused with 6-OHDA (60 microg) in the right striatum under chloral hydrate anesthesia. The rats in different groups were treated with 0, 5, 15 and 30 mg/kg QNC (i.p.) for 4 days, while first injection was given 30 min before 6-OHDA. On day 5, rats were sacrificed and striata were stored at -80 degrees C. Administration of MPTP or 6-OHDA significantly reduced striatal DA, which was significantly attenuated by QNC. Concomitant treatment with QNC also protected animals against MPTP or 6-OHDA-induced depletion of striatal GSH. Our findings clearly suggest the role of PLA2 in MPTP and 6-OHDA induced neurotoxicity and oxidative stress. However, further studies are warranted to explore the therapeutic potential of PLA2 inhibitors for the treatment of Parkinsons disease.

Vitamin E decreases valproic acid induced neural tube defects in mice

The present study was undertaken to investigate the effect of vitamin E on valproic acid (VPA) induced teratogenesis. Pregnant Balb mice were divided into six groups of 10-11 animals each. The mice in group 1 served as control and were injected with saline subcutaneously on day 8 of gestation, whereas, animals in group 2 received a single injection of VPA (700 mg/kg (s.c.)). Groups 3 and 4 received an oral administration of vitamin E in the doses of 250 and 500 mg/kg, respectively, 1 h before VPA injection. Group 5 and 6 were given vitamin E only, in the same doses as group 3 and 4. On day 18 of gestation, the mice were killed by cervical dislocation. Embryotoxicity was assessed by counting the number of implants, live and dead fetuses, resorptions, crown rump length and fetal body weight. The fetuses were observed for malformations including neural tube defects (excencephaly), open eye lid and micrognathae. VPA administration resulted in a significant reduction of the average live fetuses/litter, fetal weight and crown rump length and a significant increase in malformations (excencephaly, open eye lid and micrognathae). Concomitant administration of vitamin E significantly attenuated VPA induced decrease in the fetal weight, crown rump length and malformations.

Neuroprotective effect of nicotine against 3-nitropropionic acid (3-NP)-induced experimental Huntington's disease in rats

Nicotinic acetylcholine receptors (nAChRs) are regarded as potential therapeutic targets to control various neurodegenerative diseases. Owing to the relevance of cholinergic neurotransmission in the pathogenesis of Huntingtons disease (HD) this investigation was aimed to study the effect of nicotine, a nAChR agonist, on 3-nitropropionic acid (3-NP)-induced neurodegeneration in female Wistar rats. Systemic administration of 3-NP in rats serves as an important model of HD. The animals received subcutaneous injections of nicotine (0, 0.25, 0.50 and 1.00 mg/kg) daily for 7 days. 3-NP (25 mg/kg, i.p.) was administered daily 30 min after nicotine for the same duration. One additional group of rats served as control (vehicle only). On day 8, the animals were observed for neurobehavioral performance (motor activity, inclined plane test, grip strength test, paw test and beam balance). Immediately after behavioral studies, the animals were transcardially perfused with neutral buffered formalin (10%) and brains were fixed for histological studies. Lesions in the striatal dopaminergic neurons were assessed by immunohistochemical method using tyrosine hydroxylase (TH) immunostaining. Treatment of rats with nicotine significantly and dose-dependently attenuated 3-NP-induced behavioral deficits. Administration of 3-NP alone caused significant depletion of striatal dopamine (DA) and glutathione (GSH), which was significantly and dose-dependently attenuated by nicotine. Preservation of striatal dopaminergic neurons by nicotine was also confirmed by immunohistochemical studies. These results clearly showed neuroprotective effect of nicotine in experimental model of HD. The clinical relevance of these findings in HD patients remains unclear and warrants further studies.

CAFFEINE IMPAIRS SHORT-TERM NEUROLOGICAL OUTCOME AFTER CONCUSSIVE HEAD INJURY IN RATS

OBJECTIVEAdenosine is an endogenous neuroprotective agent that is released during ischemia, hypoxia, epilepsy, and ischemic brain injury. Caffeine is a receptor antagonist for adenosine that might interfere with the neuroprotective effect of adenosine in ischemic-hypoxic conditions. An investigation was undertaken to study the effect of caffeine on neurological function, edema formation, and blood-brain barrier permeability after experimental head injury in rats. METHODSAdult female Wistar rats classified into different groups received caffeine intraperitoneally at doses of 0, 50, 100, and 150 mg/kg body weight. Thirty minutes after the caffeine treatment, the animals were subjected to concussive head injury (CHI) administered by a controlled cortical impact device. Neurological severity score was recorded in each rat at 2 hours after CHI. Specific gravity, water content (as an indicator of edema), and blood-brain barrier impairment were analyzed in the cortical tissue surrounding the injury site. The levels of myeloperoxidase and malondialdehyde in the cortical region were measured as indicators of neutrophil infiltration and lipid peroxidation, respectively. RESULTSA significant increase in righting latency and neurological deficiency after CHI was observed in caffeine-treated rats as compared with untreated animals. Although no deaths occurred in the rats exposed to CHI after pretreatment with saline, pretreatment with caffeine caused significant mortality of animals after trauma in a dose-dependent manner. Caffeine also exacerbated neutrophil infiltration, edema, and disruption of blood-brain barrier in the traumatic cortex. Light microscopy of brain revealed more severe hemorrhage and neuronal degeneration in the injured hemisphere of caffeine-treated rats as compared with rats in the injury-alone group. A significant increase in malondialdehyde in the brain of injured rats treated with caffeine before CHI clearly indicated the role of oxidative stress. CONCLUSIONCaffeine adversely affects outcome after CHI, possibly as a result of blockade of adenosine receptors. The findings also point toward the involvement of free radical-mediated neuronal damage in caffeine-induced exacerbation of neurotrauma.

Pentoxifylline ameliorates lithium-pilocarpine induced status epilepticus in young rats

The neuroprotective effects of pentoxifylline (PTX) against lithium-pilocarpine (Li-Pc)-induced status epilepticus (SE) in young rats are described. Animals treated with PTX (0, 20, 40, and 60 mg/kg) before induction of SE were examined for latency to and frequency of SE, behavioral changes, oxidative stress, neurochemical alterations in the hippocampus and striatum, and histological abnormalities in the hippocampus. Treatment with PTX significantly ameliorated the frequency and severity of epileptic seizures in a dose-dependent manner. Our behavioral studies using the elevated plus-maze, rotarod, and water maze tests suggested a significant reduction in anxiety, enhanced motor performance, and improved learning and memory in PTX-treated rats. Li-Pc-induced neuronal cell loss and sprouting of mossy fibers in the hippocampus were also attenuated by PTX. The neuroprotective activity of PTX was accompanied by reduction in oxidative stress and reversal of SE-induced depletion of dopamine and 5-hydroxytryptamine in hippocampus and striatum. The results of this study provide a good rationale to explore the prophylactic/therapeutic potential of PTX in SE.

Citalopram, a selective serotonin reuptake inhibitor augments harmaline-induced tremor in rats.

Citalopram, a serotonin reuptake inhibitor (SSRI) is one of the widely used antidepressants. Apart from its antidepressant activity citalopram is also used for anxiety, panic disorders, obsessive-compulsive disorder and behavioral disturbances of dementia. Tremor is the second most common neurological adverse effect in patients receiving treatment with SSRIs. Use of these agents in depressed patients with essential tremor has not been studied. The present study was undertaken to investigate the effect of chronic citalopram treatment on harmaline-induced tremors in rats. Female Sprague-Dawley rats weighing 70+/-2 g were given citalopram in doses of 0, 10, 20 and 40 mg/kg by gavage for 2 weeks. On the 15th day, the rats were given harmaline (10 mg/kg, i.p.) 30 min after the last dose of citalopram. The latency of onset, intensity and duration of tremor and EMG were recorded. Serotonin (5HT) and 5-hydroxy indole acetic acid (5HIAA) were measured in brain stem. Citalopram dose dependently exacerbated the duration, intensity and amplitude of EMG of harmaline-induced tremor. A significant decrease in 5HT turnover (5HIAA/5HT ratio) in the brain stem was observed suggesting a possible role of serotoninergic impairment in citalopram-induced augmentation of harmaline-induced tremor. Clinical implications of these observations warrant further investigation.

Attenuation of iminodipropionitrile induced behavioral syndrome by sodium salicylate in rats.

Iminodipropionitrile (IDPN) produces irreversible behavioral abnormalities characterized by excitation with choreiform and circling movements (ECC) syndrome in rodents. Concomitant exposure to drugs or environmental chemicals has been shown to alter IDPN-induced neurobehavioral toxicity. This investigation was undertaken to study the effect of sodium salicylate (SS) on IDPN-induced behavioral abnormalities in rats. The animals were exposed to IDPN (100 mg/kg ip) daily for 8 days. SS was administered daily 30 min before IDPN in the doses of 50, 100 and 200 mg/kg ip for 12 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex and contact inhibition of the righting reflex. Horizontal and vertical locomotor activities and forelimbs grip strength were also measured. After behavioral studies, the animals were sacrificed, and the cerebrum and temporal bones were collected for glutathione analysis and inner ear histopathology, respectively. The onset of ECC syndrome was observed on Day 9 in the IDPN-alone group with 100% incidence on Day 12. Cotreatment with salicylate dose-dependently delayed the onset time and significantly attenuated the incidence and severity of IDPN-induced neurobehavioral signs. IDPN alone significantly increased horizontal motor activity and reduced vertical motor activity and forelimbs grip strength; these effect were significantly reversed by salicylate treatment. Treatment with salicylate also attenuated IDPN-induced depletion of GSH in the cerebrum, suggesting its free radical scavenging property.

Exacerbation of iminodipropionitrile-induced behavioral toxicity, oxidative stress, and vestibular hair cell degeneration by gentamicin in rats.

This study describes the effect of gentamicin, an aminoglycoside antibiotic on iminodipropionitrile (IDPN)-induced abnormal neurobehavioral syndrome in female Sprague-Dawley rats. The animals were exposed to IDPN in the dose of 100 mg/kg/day intraperitoneally for 7 days. Gentamicin (GM) was administered intraperitoneally daily 1 h before IDPN in the doses of 10, 40, and 80 mg/kg body weight in three different groups of rats. One more group of animals received gentamicin alone (80 mg/kg) and served as the gentamicin-alone group. The intensity of IDPN induced characteristic excitation with choreiform, and the circling movement (ECC) syndrome was examined using an observational test battery including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of the righting reflex on days 6, 8, 10, 12, 19, 26, and 33. The animals for histopathological observation were sacrificed on day 10, whereas the remaining animals that were used for long-term behavioral studies were sacrificed on day 35 for biochemical observations. The blood and brain samples were collected for the analysis of blood urea nitrogen (BUN), serum creatinine, cerebral malondialdehyde (MDA), conjugated dienes, and lipid hydroperoxides, whereas temporal bones were collected for inner ear histopathology. Our results showed that gentamicin significantly and dose dependently exacerbated the incidence and the severity of the IDPN-induced behavioral syndrome. The histopathology of the inner ear demonstrated more severe loss of sensory hair cells in the crista ampullaris of the rats treated with IDPN plus gentamicin compared to the IDPN-alone treated animals. Concomitant treatment with gentamicin also potentiated IDPN-induced increase in free radical indices, suggesting a possible role of oxidative stress in gentamicin-induced aggravation of IDPN toxicity. Further studies are warranted to determine the role of aminoglycosides in nitrile toxicity and drug-induced movement disorders.

2-Deoxy-D-glucose attenuates harmaline induced tremors in rats

Neuronal hyperactivity in essential tremor is accompanied by high energy demand in cerebellum, medulla and the thalamus. It has been suggested that brain regions that have increased metabolic demands are highly vulnerable to interruptions in glucose metabolism. In the present investigation attempt was made to study the effect of 2-deoxyglucose (2DG) a glycolytic pathway inhibitor on harmaline induced tremor in rats. Wistar rats of either sex weighing 100+/-3 g were given harmaline (10 mg/kg, i.p.) alone or along with 2DG (15 min before harmaline) in doses of 300, 600 and 900 mg/kg, respectively. The latency of onset, intensity and duration of tremor following harmaline administration were recorded. Neurobehavioral responses, electromyography (EMG) and levels of blood glucose and cerebellar serotonin (5HT) were determined after 40 min of harmaline administration. 2DG significantly and dose dependently attenuated severity of harmaline induced tremors and amplitude of EMG. Treatment of rats with 2DG alone reduced the locomotor activity, however, no significant change was observed in grip strength, landing foot splay, air righting reflex and response to tactile stimuli. Harmaline alone and along with 2DG had no effect on behavioral parameters except a decrease in landing foot splay. 2DG produced a dose-dependent hyperglycemia and attenuated harmaline induced increase in cerebellar 5HT levels. Our results clearly suggest the protective effect of 2DG in harmaline induced tremor. Further studies are warranted to assess the role of glucoprivation in the suppression of neuronal excitability in tremors.

Baclofen attenuates harmaline induced tremors in rats

Recent experimental and clinical studies clearly suggest the role of gamma-aminobutyric acid (GABA) in the pathogenesis of tremors. The present study was undertaken to investigate the effect of baclofen, a GABA B receptor agonist on harmaline induced tremors. Four groups of female Wistar rats weighing 100+/-15 g were injected with harmaline (10 mg/kg, intraperitoneally) for inducing experimental tremors. The animals in groups 2, 3 and 4 were given baclofen by gavage at doses of 2.5, 5 and 10 mg/kg, respectively, half an hour before harmaline administration, whereas, the rats in group 1 served as control and received water. The latency of onset, intensity and duration of tremor and electromyographic (EMG) responses were recorded. Treatment with baclofen resulted in a dose dependent decrease in the intensity of tremor. Our EMG study also revealed a significant decrease in the amplitude of tremors in baclofen treated rats. A highly significant increase in latency of onset of tremor was observed in the rats treated with high dose (10 mg/kg) of baclofen only. This study clearly suggests beneficial effects of baclofen in harmaline induced tremors.