Improved Locomotor Activity Research Articles

PMH63 Stay Healthy Through Game-Care Therapeutics: It's Time to Play the Game!

Health care research in present scenario is a platform wherein a range of interventions play their role to alleviate suffering and mitigate the course of diseases. Gaming console have so far demonstrated promising and considerable potential as rehabilitation and lifestyle treatments. The objective of this review was to study the advent and role of new generation gaming consoles (e.g. Nintendo Wii, Xbox, and PS3) in healthcare research in a systematic manner. A consolidated search strategy was developed and run in EMBASE, MEDLINE, Cochrane, POPLINE, SCOPUS, and Clinicaltrials.gov databases to identify the trials utilising gaming consoles as principal intervention or supportive treatment in various disease areas. Grey literature was also identified though Google Scholar. Data extraction was performed and results were summarized. The data revealed that motion sensor and interactive gaming consoles have found their role in multiple health care fields ranging from rehabilitation, weight loss, stroke recovery, improvement in locomotor activity, Parkinson's disease, Alzheimer's disease, and back pain, etc. Also, their active presence in promoting exercise, health care coaching and monitoring, and health awareness programs has seen a marked increase due to new and innovative applications being identified every day. Newer health care technologies and platforms like gaming consoles help in numerous disease area to improve patient outcomes. Their transformation, propagation, and implementation as tools of healthcare services is a valuable strategy that the health care organizations should consider taking into consideration the emerging field of gaming technology in parallel with health technology. Detailed analysis, data tables, and graphs describing the study results will be presented.

A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets

The atypical antidepressant, bupropion, causes a partial reversal of motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. However, its monoamine uptake blocking actions are believed to be mediated by the major metabolites, racemic (-)-(2R,3R)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (R,R-hydroxybupropion) and (+)-(2S,3S)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (S,S-hydroxybupropion). Therefore, we have evaluated the ability of enantiomers to improve locomotor activity and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Bupropion produced a little increase in locomotor activity and a more pronounced improvement in motor disability. The S,S-hydroxybupropion, but not the R,R-hydroxybupropion, enantiomer dose-dependently increased both locomotor activity and reversed motor disability. Combined administration of S,S-hydroxybupropion and R,R-hydroxybupropion at the same dose (analogous to the racemate) again improved motor function and to the same extent as produced by S,S-hydroxybupropion alone. The data suggest that the S,S-enantiomer of hydroxybupropion may possess potential antiparkinsonian activity.

Chronic Caloric Restriction Improves Locomotor Activity in Aging Female Mice

Caloric restriction (CR) is the most widely studied model of longevity. Aging induces alterations in behavior and reduced locomotion, i.e., bradykinesis, is a reliable biomarker of aging. CR, applied for a relatively short time (weeks to months) has been shown to improve bradykinesis, but it is not known what happens when the animals advance to old age. In order to explore the behavioral effects linked to long term CR and aging, we examined the behavior study of old (>24mo) female mice under CR since youth, with mice monitored for the same time on normal diets (ND). Average body weights fell over 2 years for CR mice (19 to 16g) and, as expected, increased for ND mice (18 to 25g). Beginning at 10 weeks of age, mice were fed either a normal diet (ND (equivalent to 10% CR)) or 40% CR and monitored up to 24 months of age. We used an open field cage system to store, replay, and analyze locomotor activity expressed as socially interactive or motile behavior. The mice under chronic CR displayed hyper‐activity (social and motile behaviors) as compared to ND mice. While comparing ND vs. 40% CR mice respectively, we detected an increase in stereotypy episodes (188 ± 13 to 458 ± 106 counts, P<0.05), movement time (658 ± 83 to 1559 ± 348 sec, P<0.05), and decrease in rest time (6540 ± 83 to 5637 ± 348 sec, P<0.05). These results suggest that increased locomotor activity is not only an early feature of CR, but persists with aging. This may not only be a biomarker for longevity, but also may be involved in the mechanism of longevity induced by CR.

Galantamine potentiates the protective effect of rofecoxib and caffeic acid against intrahippocampal Kainic acid-induced cognitive dysfunction in rat

Role of neuroinflammatory mediators particularly cyclooxygenase (COX), lipoxygenase (LOX), have been well suggested in the pathophysiology of neurodegenerative disorders. Rofecoxib is a selective cyclooxygenase 2 enzymes belongs to non-steroidal anti-inflammatory drug, commonly called as coxibs. Whereas, caffeic acid (3,4-dihydroxycinnamic acid) is one of the natural phenolic compounds and reported to inhibit 5-lipoxygenase (5-LOX) activity as one of mechanisms. Present study has been designed to investigate the effects of rofecoxib, caffeic acid and its potentiation by galantamine against intrahippocampal kainic acid-induced cognitive impairment, oxidative damage and mitochondrial respiratory enzyme alterations in rats. Kainic acid (KA) was administrated in the hippocampus region of rat brain. Various behavioral (locomotor activity and memory performances were assessed by using actophotometer and Morris water maze respectively) followed by oxidative stress, mitochondrial enzyme complex were assessed. Intrahippocampal administration of KA significantly impaired locomotor activity, memory performance, mitochondrial enzyme complexes and caused oxidative stress as compared to sham treatment. Rofecoxib (5 and 10 mg/kg), caffeic acid (5 and 10 mg/kg), Gal (2.5 and 5 mg/kg) treatment for 14 days significantly improved locomotor activity, memory retention and oxidative defense (as evidenced by decrease lipid peroxidation, nitrite, increased superoxide dismutase activity and redox ratio) in hippocampus. Besides, alterations in the levels of mitochondrial enzymes and acetylcholine esterase enzyme were significantly restored by rofecoxib and caffeic acid as compared to control. Further, combination of rofecoxib (5 mg/kg) with caffeic acid (5 mg/kg) and lower dose of gal (2.5 mg/kg) with rofecoxib (5 mg/kg) treatments significantly potentiated their protective effect which was significant as compared to their effect per se. The results of the present study suggest that galantamine potentiates the protective effect of rofecoxib and caffeic acid against kainic acid induced cognitive impairment and associated oxidative damage.

Antidepressant Effects of a Plant-Derived Flavonoid Baicalein Involving Extracellular Signal-Regulated Kinases Cascade

Depression and related mood disorders are among the world's greatest public health problems. Previous studies have demonstrated that baicalein (Bai), one plant-derived active flavonoid, exhibits neuroprotection against ischemic brain injury and stimulates the levels of phosphorylation of extracellular signal-regulated kinase (pERK) and brain-derived neurotrophic factor (BDNF) expression in vivo. In this study, the antidepressant-like effects of baicalein was investigated using acute and chronic animal models of depression. The results showed that acute application of Bai at doses of 1, 2 and 4 mg/kg by intraperitoneal injection (i.p.) significantly reduced the immobility time in the forced swimming test (FST) and tail suspending test (TST) of mice. In addition, the chronic application of Bai by i.p. for 21 d also reduced the immobility time and improved locomotor activity in chronic unpredictable mild stress (CMS) model rats. Furthermore, it was shown that Bai reversed the reduction of extracellular ERKs phosphorylation and the level of BDNF expression in the hippocampus of CMS model rats. These results suggest that Bai produce an antidepressant-like effect and this effect is at least partly mediated by hippocampal ERK-mediated neurotrophic action.

Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats

Huntington disease is a neurodegenerative disease with complex pathophysiology. Recently, role of neuroinflammation and interplay between various other cellular cascades have been suggested to be involved in pathophysiology of Huntington disease. Involvement of calcium overload mediated oxidative damage and excitotoxicity have been suggested to play a central role in quinolinic acid induced Huntington like symptoms. The present study has been carried out to investigate the neuroprotective effect of calcium channel blockers (verapamil and diltiazem) against quinolinic acid induced dysfunction in motor, biochemical and neuroinflammatory signaling in rats. Intrastriatal quinolinic acid administration leads to significant motor [locomotor (72% reduction), rotarod (55% reduction), balance beam walk performance] dysfunction coupled with the marked oxidative damage and increased neuroinflammatory markers [TNF-α (140%), IL-6 (115%), caspase-3(75%)] levels in striatum as compared to the sham treatment. Verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) drug treatment for 21days resulted in a significant improvement in the motor function (improvement in locomotor activity, rotarod and balance beam walk performance). Further, verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) treatment significantly attenuated oxidative damage, level of proinflammatory mediators (TNF-α IL-6 and caspase-3) in quinolinic acid treated animals. Results of the present study demonstrate that protective effect of these calcium channel blockers (verapamil, diltiazem) might be due to their inhibitory action on different neuroinflammatory pathways against quinolinic acid induced Huntington disease like symptoms in rats.

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.

Possible nitric oxide modulation in the protective effect of trazodone against sleep deprivation-induced anxiety like behavior and oxidative damage in mice

Purpose: The present study was designed to explore the possible nitric oxide modulation in the protective effect of trazodone against sleep deprivation-induced behavioral alterations and oxidative damage in mice. Methods: In a controlled study, sleep deprivation was induced in 10 groups of mice (6 in each group) for 72 hr by using grid suspended over water method. Trazodone (5 and 10 mg/kg, ip), L-arginine (50 mg/kg, ip), L-NAME (10 mg/kg, ip) and methylene blue (10 mg/kg, i.p) were administered for 5 days, 2 days prior to the 72 hr sleep deprivation. Various behavioral tests (plus maze, zero maze, mirror chamber, actophotometer) followed by oxidative stress parameters (malondialdehyde level, reduced glutathione, catalase, nitrite and protein) were assessed in the animals. Results: The trazodone treatment significantly indcued anti-anxiety like effect, improved locomotor activity and antioxidant effect as indicated by reduced lipid peroxidation, nitrite concentration and restoration of depleted reduced glutathione and catalase activity. Further, prior treatment of the animals with L-NAME and methylene blue potentiated the protective effect of trazodone (5 mg/kg) (p<0.05). However, L-arginine combined with trazodone (5mg/kg) reversed the protective effect of trazodone (p<0.05). Conclusion: Results of present study suggest that NO modulation is involved in the protective effect of trazodone against sleep deprivation-induced anxiety like behavior and oxidative damage in mice. Keywords: Anxiety, locomotor activity, oxidative stress, sleep deprivation, trazodone, L-arginine, L-NAME, methylene blue.

Effect of St. John's Wort (Hypericum perforatum) treatment on restraint stress-induced behavioral and biochemical alteration in mice.

BackgroundA stressful stimulus is a crucial determinant of health and disease. Antidepressants are used to manage stress and their related effects. The present study was designed to investigate the effect of St. John's Wort (Hypericum perforatum) in restraint stress-induced behavioral and biochemical alterations in mice.MethodsAnimals were immobilized for a period of 6 hr. St. John's Wort (50 and 100 mg/kg) was administered 30 minutes before the animals were subjecting to acute immobilized stress. Various behavioral tests parameters for anxiety, locomotor activity and nociceptive threshold were assessed followed by biochemical assessments (malondialdehyde level, glutathione, catalase, nitrite and protein) subsequently.Results6-hr acute restraint stress caused severe anxiety like behavior, antinociception and impaired locomotor activity as compared to unstressed animals. Biochemical analyses revealed an increase in malondialdehyde, nitrites concentration, depletion of reduced glutathione and catalase activity as compared to unstressed animal brain. Five days St. John's Wort treatment in a dose of 50 mg/kg and 100 mg/kg significantly attenuated restraint stress-induced behavioral (improved locomotor activity, reduced tail flick latency and antianxiety like effect) and oxidative damage as compared to control (restraint stress).ConclusionPresent study highlights the modest activity of St. John's Wort against acute restraint stress induced modification.

Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer

Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents its direct incorporation into an adeno-associated virus (AAV) vector for therapeutic gene transfer into muscle. To bypass this limitation, we split the dysferlin cDNA at the exon 28/29 junction and cloned it into two independent AAV vectors carrying the appropriate splicing sequences. Intramuscular injection of the corresponding vectors into a dysferlin-deficient mouse model led to the expression of full-length dysferlin for at least 1 year. Importantly, systemic injection in the tail vein of the two vectors led to a widespread although weak expression of the full-length protein. Injections were associated with an improvement of the histological aspect of the muscle, a reduction in the number of necrotic fibers, restoration of membrane repair capacity and a global improvement in locomotor activity. Altogether, these data support the use of such a strategy for the treatment of dysferlin deficiency.

Venlafaxine involves nitric oxide modulatory mechanism in experimental model of chronic behavior despair in mice

Present study has been designed to elucidate the nitric oxide modulatory mechanism of venlafaxine in experimental model of chronic behavior despair in mice. Animals (male albino laca mice) were forced to swim daily for 6 min test session for 7 days and immobility period of each animal was measured on every alternate days. Six minutes forced swimming test session for 7 days caused anxiety-like behavior (as assessed by mirror chamber and plus maze tests) and impairment in locomotor activity followed by oxidative damage (increased lipid peroxidation, nitrite concentration, depleted reduced glutathione and catalase activity) as compared to naïve animals. Seven days venlafaxine (5 and 10 mg/kg) treatment significantly caused anti-anxiety-like effect, improved locomotor activity and attenuated oxidative damage (reduced lipid peroxidation, nitrite concentration and caused restoration of reduce glutathione and catalase activity) as compared to control. Caffeine (10 mg/kg) pretreatment with venlfaxine (5 mg/kg) did not produce any significant effect on locomotor activity, immobility period and oxidative damage as compared to their effect per se. Further, l-NAME (5 mg/kg) and methylene blue (10 mg/kg) pretreatment with sub effective dose of venlafaxine (5 mg/kg) potentiated its protective effect which was significant as compared to their effect per se. However, l-arginine (100 mg/kg) pretreatment with venlafaxine (5 mg/kg) significantly reversed the protective effect of venlafaxine ( P < 0.05). Present study suggests that nitric oxide modulation might be involved in the protective effects of venlafaxine.

Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model

Background Gene therapy is considered one of the most promising approaches to develop an effective treatment for Parkinson's disease (PD). The existence of blood-brain barrier (BBB) significantly limits its development. In this study, lactoferrin (Lf)-modified nanoparticles (NPs) were used as a potential non-viral gene vector due to its brain-targeting and BBB-crossing ability. Methods and results The neuroprotective effects were examined in a rotenone-induced chronic rat model of PD after treatment with NPs encapsulating human glial cell line-derived neurotrophic factor gene ( hGDNF) via a regimen of multiple dosing intravenous administration. The results showed that multiple injections of Lf-modified NPs obtained higher GDNF expression and this gene expression was maintained for a longer time than the one with a single injection. Multiple dosing intravenous administration of Lf-modified NPs could significantly improve locomotor activity, reduce dopaminergic neuronal loss, and enhance monoamine neurotransmitter levels on rotenone-induced PD rats, which indicates its powerful neuroprotective effects. Conclusion The findings may have implications for long-term non-invasive gene therapy for neurodegenerative diseases in general.

T.O.2 Efficient recovery of dysferlin deficiency by dual adeno associated vector mediated gene transfer

Deficiency of the dysferlin protein presents as two major clinical phenotypes: Limb Girdle Muscular Dystrophy type2B (LGMD2B) and Miyoshi Myopathy (MM). Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents its direct incorporation into an Adeno-Associated-Virus (AAV) vector for therapeutic gene transfer into muscle. To bypass this limitation, we split the dysferlin cDNA at the exon 28/29 junction and cloned it into two independent AAV vectors carrying the appropriate splicing sequences. Transfer of the corresponding vectors into a dysferlin-deficient mouse model led to the expression of full-length dysferlin for at least one year. This expression was associated with an improvement of the histological aspect of the muscle, a reduction in the number of necrotic fibers, restoration of membrane repair capacity and a global improvement in locomotor activity. Altogether, these data support the use of such a strategy for the treatment of dysferlin deficiency.

Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation–induced behaviour modification and oxidative damage in mice

Sleep is an important physiological process responsible for the maintenance of physical, mental and emotional health of a living being. Sleep deprivation is considered risky for several pathological diseases such as anxiety and motor and cognitive dysfunctions. Sleep deprivation has recently been reported to cause oxidative damage. This study has been designed to explore the possible involvement of the GABAergic mechanism in protective effects of melatonin against 72-h sleep deprivation-induced behaviour modification and oxidative damage in mice. Mice were sleep-deprived for a period of 72 h using the grid over water suspended method. Animals were divided into groups of 6-8 animals each. Melatonin (5 and 10 mg/kg), flumazenil (0.5 mg/kg), picrotoxin (0.5 mg/kg) and muscimol (0.05 mg/kg) were administered for 5 days starting 2 days before 72-h sleep deprivation. Various behavioural tests (plus maze, zero maze, mirror chamber, actophotometer) and body weight assessment followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were carried out. The 72-h sleep deprivation caused significant anxiety-like behaviour, weight loss, impaired locomotor activity and oxidative damage as compared with naïve (without sleep deprivation). Treatment with melatonin (5 mg/kg and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared with control (sleep-deprived). Biochemically, melatonin treatment significantly restored reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared with control animals (72-h sleep-deprived). Flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) pretreatments with a lower dose of melatonin (5 mg/kg) significantly antagonized the protective effect of melatonin. However, muscimol (0.05 mg/kg) pretreatment with melatonin (5 mg/kg, ip) potentiated the protective effect of melatonin which was significant as compared with their effect per se. This study suggests that GABAergic modulation is involved in the protective action of melatonin against sleep deprivation-induced anxiety-like behaviour and associated oxidative damage.

Protective effect of naringin against ischemic reperfusion cerebral injury: Possible neurobehavioral, biochemical and cellular alterations in rat brain

The present study was conducted with an aim to explore the possible role of naringin against ischemia reperfusion induced-neurobehavioral alterations, oxidative damage, cellular and histopathological alterations in cortex, striatum, hippocampus areas of brain. Male Wistar rats (200–220 g) were subjected to bilateral carotid artery occlusion for 30 min followed by reperfusion for 24 h to induce reperfusion (I/R) cerebral injury. Naringin (50, 100 mg/kg, i.p.) was administered for 7 days continuously before animals were subjected to ischemia reperfusion injury. Various behavioral tests [locomotor activity, neurological score (inclined beam test), transfer latency, resistance to lateral push] and biochemical parameters (lipid peroxidation, nitrite level, reduced glutathione, superoxide dismutase and catalase activity), mitochondrial enzyme dysfunctions (Complex I, II, III and IV) in cortex, striatum, hippocampus of brain and histopathological alterations were assessed subsequently. Seven days naringin (50 and 100 mg/kg) treatment significantly improved neurobehavioral alterations (improved locomotor activity, inclined beam walking and reduced resistance to lateral push, transfer latency) as compared to control ischemia reperfusion. Naringin (50 mg/kg and 100 mg/kg) treatment significantly attenuated oxidative damage as indicated by reduced lipid peroxidation, nitrite concentration, restored reduced glutathione and catalase activity and mitochondrial enzyme activities in cortex, striatum, cerebellum as compared to control (ischemia reperfusion) animals. In addition, naringin treatment significantly reversed histopathological alterations in cortex, striatum, hippocampus areas as compared to control (ischemia reperfusion). Present study suggests the protective effect of naringin and its therapeutic potential against ischemia reperfusion induced and related behavioral alterations in rats.

Neuroprotection in a 6‐hydroxydopamine‐lesioned Parkinson model using lactoferrin‐modified nanoparticles

Nonviral gene therapy of chronic degenerative diseases such as Parkinson's disease (PD) is a great challenge as a result of the low tranfection efficiency of nonviral gene vectors. We previously constructed a lactoferrin (Lf)-modified vector, which was demonstrated to be potential for brain gene delivery both in vitro and in vivo. In the present study, this type of vector was applied to load human glial cell line-derived neurotrophic factor gene (hGDNF). A rat PD model was constructed by the unilateral lesion of striatum using 6-hydroxydopamine (6-OHDA). Lf-modified nanoparticles (NPs) were prepared and characterized. Neuroprotective effects of Lf-modified NPs were examined in the 6-OHDA-lesioned PD model via a regimen of multiple dosing intravenous administrations. The size of Lf-modified NPs was 196 +/- 10.1 nm, whereas the zeta potential value was 29.35 +/- 3.27 mV. Lf-modified NPs could protect themselves from heparin displacement and DNase digestion. The results of the neuroprotective evaluation show that increasing the number of injections of Lf-modified NPs loading hGDNF improved locomotor activity, reduced dopaminergic neuronal loss and enhanced monoamine neurotransmitter levels in PD rats. Five injections of Lf-modified NPs loading hGDNF exhibited much more powerful neuroprotection than a single injection, indicating the effectiveness and feasibility of multiple dosing administrations. The results of toxicity tests demonstrated that the dosage of NPs used in the present study was safe enough for brain gene delivery. The findings obtained in the present study suggest that Lf-modified NPs could be developed for potential nonviral gene therapy of chronic brain disorders.

Axonal Outgrowth and Erk1/2 Activation by Training after Spinal Cord Injury in Rats

Abstract Physical training in experimental animals can improve locomotor activity via the regulation of spinal neural circuitry or peripheral nerve regeneration. Here we investigated the effects of treadmill training (TMT) on regenerative responses of the corticospinal tract (CST) after contusive spinal cord injury (SCI). One week after injury of the low thoracic spinal cord, rats were given TMT or sedentary treatment for 1-4 weeks. Anterograde tracing of descending CST axons revealed that TMT enhanced collateral arborization of CST axons surrounding the injury cavity and promoted extension into the caudal spinal cord. The number of oligodendrocytes in the vicinity of the injury cavity was significantly increased at 2 or 4 weeks after TMT compared to sedentary controls. The data further showed that TMT increased phosphorylation of Erk1/2 in the motor cortex as well as the spinal cord injury area, and inhibition of Erk1/2 activity by administration of the MEK1 inhibitors PD98059 and U0126 reduced collateral outgrowth of descending CST axons in TMT animals. TMT for 2-4 weeks significantly improved behavioral scores as assessed by the Basso-Beattie-Bresnahan scale, as well as on motor function and gridwalk testing. Our data imply that Erk1/2 may be an important mediator for transmitting signals from the injury site to the cell body, and further suggest that activation of the Erk1/2 signaling pathway may be involved in enhanced outgrowth of CST axons after TMT.

Protective effects of antidepressants against chronic fatigue syndrome – induced behavioral changes and biochemical alterations

Chronic fatigue syndrome (CFS) is characterized by profound fatigue, which substantially interferes with daily activities. The aim of this study was to explore the protective effects of antidepressants in an animal model of CFS in mice. Male albino mice were forced to swim individually for a period of 6-min session each for 7 days. Imipramine (10 and 20 mg/kg), desipramine (10 and 20 mg/kg) and citalopram (5 and 10 mg/kg) were administered 30 min before forced swimming test on each day. Various behavior tests (immobility time, locomotor activity, anxiety-like behavior by plus maze and mirror chamber) followed by biochemical parameters (lipid peroxidation, reduced glutathione, catalase and nitrite level) were assessed in chronic stressed mice. Chronic forced swimming for 7 days significantly caused increase in immobility period, impairment in locomotor activity, anxiety-like behavior, and oxidative stress (raised lipid peroxidation, nitrite activity and reduced glutathione and catalase activity) as compared with naïve mice (P < 0.05). Seven days of pretreatment with imipramine (10 and 20 mg/kg), desipramine (10 and 20 mg/kg), and citalopram (5 and 10 mg/kg) significantly reduced immobility time, improved locomotor activity and anti-anxiety effect (in both plus maze and mirror chamber test), and attenuated oxidative stress in chronic stressed mice as compared with control (chronic fatigues) (P < 0.05). These results suggested that these drugs have protective effect and could be used in the management of chronic fatigue like conditions.

Combined hematopoietic and lentiviral gene‐transfer therapies in newborn Twitcher mice reveal contemporaneous neurodegeneration and demyelination in Krabbe disease

This study characterized the therapeutic benefits of combining hematogenous cell replacement with lentiviral-mediated gene transfer of galactosylceramidase (GALC) in Twitcher mice, a bona fide model for Krabbe disease. Bone marrow cells and GALC-lentiviral vectors were administered intravenously without any preconditioning to newborn Twitcher pups before postnatal day 2. Treated Twitchers survived up to 4 months of age. GALC activity remained less than 5% of normal values in the nervous system for the first 2 months after treatment and reached approximately 30% in long-term-surviving mice. Long-term reconstitution of GALC activity in the nervous system was provided primarily by infiltrating macrophages and to a lesser extent by direct lentiviral transduction of neural cells. Treated Twitchers had significant preservation of myelin, with a G-ratio (ratio of the axon diameter to the diameter of the myelinated fiber) in sciatic nerve myelin of 0.75 +/- 0.08 compared with 0.85 +/- 0.10 in untreated mutants. Although treated mutants had improved locomotor activities during their long-term survival, they died with symptoms of progressive neurological degeneration, indistinguishable from those seen in untreated Twitchers. Examination of long-lived Twitchers showed that treated mutants were not protected from developing degeneration of axons throughout the neuroaxis. These results suggest that GALC deficiency not only affects myelinating glia but also leads to neuronal dysfunction. The contemporaneous neuropathology might help to explain the limited efficacy of current gene and cell therapies.

Diacerein mutual prodrug for osteoarthritis: synthesis, in vitro kinetic studies and preliminary pharmacological screening

Abstract A gastro-sparing diacerein mutual prodrug was designed and synthesized by linking it to D-glucosamine as a promoiety with an objective of increasing the potential of its anti-inflammatory activity and improving its hydrophilic characteristics so as to make its parenteral administration feasible. Diacerein was linked with D-glucosamine through amide linkage and was subjected to in vitro release studies in aqueous buffers of varied pH range. 97% release of diacerein was achieved in phosphate buffer (pH 7.4) with a half-life of 48 min, following first order kinetics. Preliminary screening was carried in a one-month study in experimental osteoarthritis in rats induced by mono-iodoacetate and therapeutic efficacy of the conjugate was evaluated for changes in knee-diameter, spontaneous locomotor activity, alkaline phosphatase and glucosaminoglycan levels. The prodrug was also tested for anti-inflammatory activity in Freund’s adjuvant arthritis and local irritant effect on rat stomach by Rainsford’s cold stress method. The prodrug exhibited quicker onset of action than diacerein with respect to reduction in knee diameter, improved locomotor activity, better anti-inflammatory and gastro-sparing activity. The preliminary results are promising. In vivo kinetic studies and evaluation in mono-iodoacetate induced osteoarthritis over a period of three months is in progress to establish its effectiveness in the management of osteoarthritis.