Luteolin-7-O-glucoside protects dopaminergic neurons by activating estrogen-receptor-mediated signaling pathway in MPTP-induced mice.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Accumulating evidences implicate the beneficial role of estrogen in the therapy of PD. METHODS: In the present study, the protective function of luteolin-7-O-glucoside (LUT-7G), a natural flavonoid, was investigated in 1-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mice. RESULTS: Pre-treatment of LUT-7G increased the viability and reduced the apoptosis of SH-SY5Y cells treated by MPP+. At molecular level, the Bcl-2/Bax ratio was increased, while the expression of cleaved caspase 3 was markedly lessened. Moreover, LUT-7G increased the expression of estrogen receptor (ER), ERα and ERß, and enhanced the activation of ERK1/2/STAT3/c-Fos that could be abolished by ER antagonists. Furthermore, in vivo experiment indicated that pre-treatment of LUT-7G improved the bradykinesia, and enhanced the muscle strength as well as the balancing capacity of mice treated with MPTP. And LUT-7G prevented the injury of TH positive cells in substantia nigra and increased TH positive nerve fibers in striatum. In addition, pre-treatment of LUT-7G also significantly diminished the MPTP-induced gliosis in substantia nigra. CONCLUSIONS: LUT-7G effectively protected dopaminergic neurons against MPP+ or MPTP-induced toxicity, probably by activating the ER-mediated signaling pathway. Our findings explore the therapeutic potential of LUT-7G for PD therapy.

Effects of agomelatine in rotenone-induced Parkinson's disease in rats.

The effects of melatonin and melatonin analogs in experimental Parkinson's disease (PD) models remain controversial. Agomelatine, a novel analog of melatonin, is both agonists for melatonin-1 and melatonin-2 receptors and antagonist of 5-HT2C receptors. While agomelatine has been commonly used as an anti-depressant and sleep drug, information about effects of agomelatine in PD are still lacking. Male Sprague-Dawley rats (220-260 g) were injected with rotenone (0.5 µg, n = 16) or vehicle (1 µl DMSO, n = 8) into the left substantia nigra (SN) and ventral tegmental area under stereotaxic surgery. After ten days, the rats were assessed for the confirmation of PD by the rotational test following apomorphine injection (2 mg/kg, i.p.). The confirmed rats were divided into two groups which received daily p.o. agomelatine (40 mg/kg, n = 8) or saline (2 ml/rat, n = 8) for consecutively 18 days. Twenty-four hours after the last drug administration, the rotational test was repeated and motor coordination was assesed just before the decapitation. Brain tissues were taken for biochemical, molecular and histopathological evaluations. Agomelatine treated animals showed augmented apomorphine-induced rotation response and impaired motor coordination compared to the rotenone group. Furthermore, agomelatine treatment significantly induced apoptosis with an increase in caspase-3 expression independent from PARP-1 activation. Agomelatine treatment caused increased protein oxidation levels, in addition to a decrease in neuron number in the striatum. Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson's disease pathology.

Initiation of calorie restriction in middle-aged male rats attenuates aging-related motoric decline and bradykinesia without increased striatal dopamine.

Aging-related bradykinesia affects ∼ 15% of those reaching age 65 and 50% of those reaching their 80s. Given this high risk and lack of pharmacologic therapeutics, noninvasive lifestyle strategies should be identified to diminish its risk and identify the neurobiological targets to reduce aging-related bradykinesia. Early-life, long-term calorie restriction (CR) attenuates aging-related bradykinesia in rodents. Here, we addressed whether CR initiation at middle age could attenuate aging-related bradykinesia and motoric decline measured as rotarod performance. A 30% CR regimen was implemented for 6 months duration in 12-month-old male Brown-Norway Fischer 344 F1 hybrid rats after establishing individual baseline locomotor activities. Locomotor capacity was assessed every 6 weeks thereafter. The ad libitum group exhibited predictably decreased locomotor activity, except movement speed, out to 18 months of age. In contrast, in the CR group, movement number and horizontal activity did not decrease during the 6-month trial, and aging-related decline in rotarod performance was attenuated. The response to CR was influenced by baseline locomotor activity. The lower the locomotor activity level at baseline, the greater the response to CR. Rats in the lower 50th percentile surpassed their baseline level of activity, whereas rats in the top 50th percentile decreased at 6 weeks and then returned to baseline by 12 weeks of CR. We hypothesized that nigrostriatal dopamine tissue content would be greater in the CR group and observed a modest increase only in substantia nigra with no group differences in striatum, nucleus accumbens, or ventral tegmental area. These results indicate that initiation of CR at middle age may reduce aging-related bradykinesia, and, furthermore, subjects with below average locomotor activity may increase baseline activity. Sustaining nigral dopamine neurotransmission may be one component of preserving locomotor capabilities during aging.

Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model.

The primary aim of this study was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the brain targeting efficiency of bromocriptine (BRC) following intranasal (i.n.) administration. The BRC loaded chitosan nanoparticles (CS NPs) were prepared by ionic gelation of CS with tripolyphosphate anions. These NPs had a mean size (161.3 ± 4. 7 nm), zeta potential (+40.3 ± 2.7 mV), loading capacity (37.8% ± 1.8%) and entrapment efficiency (84.2% ± 3.5%). The oral administration of haloperidol (2mg/kg) to mice produced typical Parkinson (PD) symptoms. Catalepsy and akinesia outcomes in animals receiving BRC either in solution or within CS NPs showed a reversal in catalepsy and akinesia behavior when compared to haloperidol treated mice, this reversal being specially pronounced in mice receiving BRC loaded CS NPs. Biodistribution of BRC formulations in the brain and blood of mice following i.n. and intravenous (i.v.) administration was performed using optimized technetium labeled (99mTc-labeled) BRC formulations. The brain/blood ratio of 0.47 ± 0.04, 0.69 ± 0.031, and 0.05 ± 0.01 for BRC solution (i.n.), BRC loaded CS NPs (i.n.) and (i.v.) respectively, at 0.5h are suggestive of direct nose to brain transport bypassing the blood-brain barrier. Gamma scintigraphy imaging of mice brain following i.v. and i.n. administrations were performed to determine the localization of drug in brain. The drug targeting index and direct transport percentage for BRC loaded CS NPs following i.n. route were 6.3 ± 0.8 and 84.2% ± 1.9%. These encouraging results confirmed the development of a novel non-invasive nose to brain delivery system of BRC for the treatment of PD.

A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism.

Erythropoietin (Epo) is neuroprotective in a number of preparations, but can lead to unacceptably high and even lethal hematocrit levels. Recent reports show that modified Epo variants confer neuroprotection in models of glaucoma and retinal degeneration without raising hematocrit. In this study, neuroprotective effects of two Epo variants (EpoR76E and EpoS71E) were assessed in a model of Parkinson's disease. The constructs were packaged in recombinant adeno-associated viral (rAAV) vectors and injected intramuscularly. After 3 weeks, mice received five daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were killed 5 weeks later. The MPTP-lesioned mice pretreated with rAAV.eGFP (negative control) exhibited a 7- to 9-Hz tremor and slower latencies to move on a grid test (akinesia). Both of these symptomatic features were absent in mice pretreated with either modified Epo construct. The rAAV.eGFP-treated mice lesioned with MPTP exhibited a 41% reduction in tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rAAV.EpoS71E construct did not protect nigral neurons, but neuronal loss in mice pretreated with rAAV.EpoR76E was only half that of rAAV.eGFP controls. Although dopamine levels were normal in all groups, 3,4-dihydroxyphenylacetic acid (DOPAC) was significantly reduced only in MPTP-lesioned mice pretreated with rAAV.eGFP, indicating reduced dopamine turnover. Analysis of TH-positive fibers in the striatum showed normalized density in MPTP-lesioned mice pretreated with rAAV.EpoS71E, suggesting that enhanced sprouting induced by EpoS71E may have been responsible for normal behavior and dopaminergic tone in these mice. These results show that systemically administered rAAV-generated non-erythropoietic Epo may protect against MPTP-induced parkinsonism by a combination of neuroprotection and enhanced axonal sprouting.

Properties of 3-methyl-TIQ and 3-methyl-N-propargyl-TIQ for preventing MPTP-induced parkinsonism-like symptoms in mice.

BACKGROUND: Selegiline, a therapeutic drug for Parkinson's disease (PD), structurally resembles the endogenous parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline (TIQ). In the present study, we evaluated the effects of 3-methyl-TIQ (3-MeTIQ) and 3-methyl-N-propargyl-TIQ (3-Me-N-proTIQ), selegiline mimetic TIQ derivatives, for preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism-like symptoms in mice. METHODS: We evaluated the preventative effects of 3-MeTIQ and 3-Me-N-proTIQ on MPTP-induced bradykinesia and depletion of striatal dopamine (DA) and nigral tyrosine hydroxylase (TH)-positive cells. RESULTS: MPTP-induced bradykinesia was not different when mice were pretreated with 3-MeTIQ, except for the high-dose group. However, pretreatment with 3-Me-N-proTIQ significantly prevented the appearance of this akinesic status. MPTP-induced striatal DA and 3,4-dehydroxyphenylacetic acid reduction were significantly prevented by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ, in a dose-dependent manner. On the other hand, levels of serotonin and its metabolite, 5-hydroxyindole acetic acid, in the striatum were increased following treatment with 3-MeTIQ. In addition, the MPTP-induced decrease in TH-positive cells in the substantia nigra was significantly reduced by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ. CONCLUSIONS: These results suggest that not only does 3-Me-N-proTIQ have potential as a candidate compound for disease-modifying therapy for PD, but also the N-propargyl functional group plays an important role in neuroprotection.

Acetyl-L-carnitine and α-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson's disease therapy.

Although the mechanisms of neurodegeneration in Parkinson's disease are not fully understood, mitochondrial dysfunction, oxidative stress and environmental toxins may be involved. The current research was directed to investigate the protective role of two bioenergetic antioxidants, acetyl-L-carnitine and α-lipoic acid, in rotenone-parkinsonian rats. Ninety six male rats were divided into five groups. Group I is the vehicle-injected group, group II is the disease control group and was injected with six doses of rotenone (1.5 mg/kg/48 h, s.c.). Groups III, IV and V received rotenone in addition to acetyl-L-carnitine (100 mg/kg/day, p.o.), α-lipoic acid (50 mg/kg/day, p.o.) or their combination, respectively. Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field and square bridge tests. In addition, ATP level was decreased whereas lipid peroxides and protein carbonyls increased in the striata of rotenone-treated rats as compared to vehicle-treated rats. Treatment with acetyl-L-carnitine or α-lipoic acid improved the motor performance and reduced the level of lipid peroxides in rat brains as compared to rotenone group. Further, ATP production was enhanced along with acetyl-L-carnitine treatments (p≤0.05). Taken together, our study reinforces the view that acetyl-L-carnitine and α-lipoic acid are promising candidates for neuroprotection in Parkinson's disease.

Demand driven deep brain stimulation: regimes and autoregressive hidden Markov implementation.

Deep brain stimulation is an increasingly prevalent surgical option in the treatment of a multitude of neurological conditions, most notably Parkinson's disease. The development of a neurofeedback device is driven primarily by stimulator habituation, surgical risk factors, the cost of battery replacement, and reported neuropsychiatric side-effects under prolonged chronic administration. Here we present two distinct regimes for stimulation delivery in chronic and acute symptomatic conditions, presented in the context of Parkinsonian bradykinesias and tremor. Implementation strategies are discussed with a focus on vector-autoregressive hidden Markov models for tremor prediction. Detection of simple motor actions versus tremor are compared in a preliminary performance analysis.

La locura tensa / The tight madness

La catatonía es considerada un síndrome neuropsiquiátrico; su diagnóstico requiere de determinados síntomas y signos cardinales que incluyen alteraciones en el afecto y en la expresión voluntaria del pensamiento y de la conducta motora.Se intenta hacer un aporte a la clínica infanto-juvenil y a la terapéutica psicofarmacológica, a través de la presentación un caso clínico de una paciente de 17 años con retraso mental internada por un cuadro de catatonía, desencadenado tras episodios de abuso sexual. Se utiliza el material de la historia clínica para mostrar los diferentes aspectos clínicos de este cuadro y su respuesta terapéutica.A partir de su ingreso a la guardia, con un cuadro catatónico, se instala un abordaje multidisciplinario con un plan farmacológico que incluye benzodiazepinas, IRSS y un antipsicótico atípico. En la evolución, se aprecia una mejoría lenta y paulatina, tanto de los síntomas motores como afectivos. Al alta, permanecen síntomas residuales, principalmente cognitivos (retraso mental). El SPECT muestra alteraciones de la perfusión en diferentes áreas (disminución, aumento y asimetría). Los síntomas motores podrían explicarse por la alteración en la regulación GABAérgica de circuitos córtico-subcorticales (circuito motor, corteza motora/premotora con los ganglios basales). A su vez, es posible que la disfunción GABAérgica del circuito prefrontal-orbitofrontal explique los síntomas afectivos y comportamentales observados.Los factores psicosociales pueden actuar como desencadenantes del cuadro por estrés crónico. La asociación de benzodiazepinas, un IRSS y un antipsicótico atípico demostró ser útil en este caso grave.(AU)

Catatonia is considered a neuropsychiatric syndrome: its diagnosis requires certain cardinal signs and symptoms which include alterations in affect and expression of thought and voluntary motor behavoir. It tries to make a contribution to the clinical child/youth and psychopharmacological treatment through a clinical case of a 17 year old patient hospitalized with mental retardation by a catatonia syndrome triggered by repeated episodes of sexual abuse. It uses material from the clinical history to show the different aspect this condition and the therapeutic response. Since its entry into the guard with a catatonic syndrome, it installs a multidisciplinary approach with a drug plan in evolution, we see a slow and gradual improvement of both motor and affective symptoms. At dishcarge residual symptoms remains, mainly cognitive (mental retardation). The SPECT shows perfusion abnormalities in different areas (decrease, increase and asymmetry). Motor symptoms may be explained by the altered regulation of GABAergic cortico-subcortical circuits, especially those which connects the motor-premotor cortex with the basal ganglia. In turn, it is possible that GABAergic dysfunction in the prefrontal-orbitofrontal cortex circuit explain emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral simptoms observed. The association of benzodiazepines, an SSRI and an atypical antipsychotic proved useful in this case serious.(AU)

La locura tensa / The tight madness

La catatonía es considerada un síndrome neuropsiquiátrico; su diagnóstico requiere de determinados síntomas y signos cardinales que incluyen alteraciones en el afecto y en la expresión voluntaria del pensamiento y de la conducta motora.Se intenta hacer un aporte a la clínica infanto-juvenil y a la terapéutica psicofarmacológica, a través de la presentación un caso clínico de una paciente de 17 años con retraso mental internada por un cuadro de catatonía, desencadenado tras episodios de abuso sexual. Se utiliza el material de la historia clínica para mostrar los diferentes aspectos clínicos de este cuadro y su respuesta terapéutica.A partir de su ingreso a la guardia, con un cuadro catatónico, se instala un abordaje multidisciplinario con un plan farmacológico que incluye benzodiazepinas, IRSS y un antipsicótico atípico. En la evolución, se aprecia una mejoría lenta y paulatina, tanto de los síntomas motores como afectivos. Al alta, permanecen síntomas residuales, principalmente cognitivos (retraso mental). El SPECT muestra alteraciones de la perfusión en diferentes áreas (disminución, aumento y asimetría). Los síntomas motores podrían explicarse por la alteración en la regulación GABAérgica de circuitos córtico-subcorticales (circuito motor, corteza motora/premotora con los ganglios basales). A su vez, es posible que la disfunción GABAérgica del circuito prefrontal-orbitofrontal explique los síntomas afectivos y comportamentales observados.Los factores psicosociales pueden actuar como desencadenantes del cuadro por estrés crónico. La asociación de benzodiazepinas, un IRSS y un antipsicótico atípico demostró ser útil en este caso grave.

Catatonia is considered a neuropsychiatric syndrome: its diagnosis requires certain cardinal signs and symptoms which include alterations in affect and expression of thought and voluntary motor behavoir. It tries to make a contribution to the clinical child/youth and psychopharmacological treatment through a clinical case of a 17 year old patient hospitalized with mental retardation by a catatonia syndrome triggered by repeated episodes of sexual abuse. It uses material from the clinical history to show the different aspect this condition and the therapeutic response. Since its entry into the guard with a catatonic syndrome, it installs a multidisciplinary approach with a drug plan in evolution, we see a slow and gradual improvement of both motor and affective symptoms. At dishcarge residual symptoms remains, mainly cognitive (mental retardation). The SPECT shows perfusion abnormalities in different areas (decrease, increase and asymmetry). Motor symptoms may be explained by the altered regulation of GABAergic cortico-subcortical circuits, especially those which connects the motor-premotor cortex with the basal ganglia. In turn, it is possible that GABAergic dysfunction in the prefrontal-orbitofrontal cortex circuit explain emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral simptoms observed. The association of benzodiazepines, an SSRI and an atypical antipsychotic proved useful in this case serious.

Preventative effects of 1,3-dimethyl- and 1,3-dimethyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on MPTP-induced Parkinson's disease-like symptoms in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is well known as an exogenous dopaminergic neurotoxin that induces Parkinson's disease-like symptoms. In addition, 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been investigated as endogenous MPTP mimetic compounds that structurally resemble selegiline, a commercially available drug for treating Parkinson's disease. In the present study, we examined the ability of 1,3-dimethyl-TIQ (1,3-diMeTIQ) and 1,3-dimethyl-N-propargyl-TIQ (1,3-diMe-N-proTIQ) to prevent MPTP-induced Parkinson's disease-like symptoms in mice and to prevent 1-methyl-4-phenylpyridinium ion (MPP+, an active metabolite of MPTP)-induced cytotoxicity in vitro, including its structural stereoselectivity. Repeated administration of MPTP induced bradykinesia, a symptom of behavioral abnormality; this was prevented by both 1,3-diMeTIQ and 1,3-diMe-N-proTIQ pretreatments. Pretreatment with 1,3-diMeTIQ did not prevent the MPTP-induced decrease in dopamine content in the striatum or the decrease in the number of tyrosine hydroxylase-positive cells in the substantia nigra. On the other hand, 1,3-diMe-N-proTIQ prevented these Parkinson's disease-like symptoms; in particular, the trans-isomer of this agent showed potent protective effects. However, the ability of the trans-1,3-diMe-N-proTIQ isomer to prevent MPP+-induced PC12 cell death was weaker than that of its cis-isomer. Thus, stereoisomers of 1,3-diMe-N-proTIQ exhibit different effects; cis-1,3-diMe-N-proTIQ inhibits MPP+-induced cytotoxicity while trans-1,3-diMe-N-proTIQ exhibits neuroprotective effects primarily through MPTP-related biological events in mice. These results also indicate the possibility of utilizing, at least in part, the stereoselective efficacy of 1,3-diMe-N-proTIQ against MPTP and/or MPP+-induced adverse states.

Effects of glutamate and alpha2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats.

Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic alpha9/alpha10 and 5-HT3 receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone+saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.

Effect of bilateral subthalamic nucleus stimulation on levodopa-unresponsive axial symptoms in Parkinson's disease.

BACKGROUND: The levodopa responsiveness of motor, particularly axial symptoms is a good predictor of the effectiveness of subthalamic nucleus (STN) stimulation in patients with Parkinson's disease (PD). However, many Japanese PD patients are intolerant of higher doses of antiparkinsonian drugs and some aspects of their axial symptoms may remain unresponsive to treatment. We retrospectively investigated the effects of bilateral STN stimulation on the axial signs unresponsive to levodopa in Japanese patients with PD. METHODS: We enrolled 29 consecutive patients into this study. Six independent axial symptoms, i.e. falling, freezing, gait, standing, posture, and postural instability, were scored on the Unified Parkinson's Disease Rating Scale (UPDRS), before and 3 months after bilateral STN stimulation and differences were statistically analysed. FINDINGS: Postoperatively, the mean levodopa dosage was decreased by 27%. The preoperative responsiveness to antiparkinsonian drugs with respect to freezing, gait, posture, and postural instability were positively correlated with postoperative off-medication improvement (p < 0.05). For each individual axial symptom, some patients showed an excellent response to STN stimulation, despite preoperative unresponsiveness to levodopa. These selected patients were not always treated with lower doses of antiparkinsonian drugs preoperatively, but they had milder preoperative scores on the UPDRS with respect to daily activities and overall axial function. CONCLUSIONS: The axial symptoms of PD unresponsive to levodopa were ameliorated by bilateral STN stimulation in patients manifesting a milder degree of preoperative axial signs. Our findings suggest that STN stimulation exerted a definite but limited effect on levodopa-unresponsive axial features, pointing to the need to identify different target structures that control axial functions via non-dopaminergic systems.

The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys.

Cholinergic receptors (AChR) are reported altered in brains from schizophrenic patients, and a growing body of evidence suggests that muscarinic receptor agonists exhibit antipsychotic potential. Centrally acting selective muscarinic receptor agonists are currently not available for clinical use, but acetylcholinesterase (AChE) inhibitors, which indirectly stimulate AChR by blocking the breakdown of acetylcholine by AChE, are widely used in the clinic against Alzheimer's disease. AChE inhibitors have been reported to exhibit antipsychotic efficacy in Alzheimer's disease patients, and these compounds have also been investigated as adjunctive treatment to antipsychotic medication in schizophrenic patients with varying results. However, monotherapy with AChE inhibitors in schizophrenic patients has not been evaluated. We wanted to investigate the antipsychotic potential of the AChE inhibitor galantamine, which also allosterically potentiates nicotinic receptor stimulation. To this end, we investigated its ability to antagonize d-amphetamine-induced psychotic-like behavior in extrapyramidal side effects (EPS)-primed Cebus monkeys. Galantamine inhibited d-amphetamine-induced unrest, arousal, and stereotypy. Side effects such as emesis, sedation, and EPS were minor or not existing. The results indicate that AChE inhibitors have antipsychotic potentials and suggest that clinical trials investigating antipsychotic effects of AChE inhibitors as monotherapy would be of interest.

[Body fluids ratio and postural stability of head-down tilted apes in the periods of transition into the active vertical position].

It is known that the hypokinetic syndrome and alteration of the hydrostatic component by microgravity distort functioning of various body systems. Prevention of the adverse effects is achieved through implementation of a variety of physical exercises during tilting, and periodic transition into the upright position. The investigation was performed with 11 Macaques (Macaca mulatta) 3 to 5 yrs. of age and 3.2-7.2 kg of weight. Brief (for 30 to 120 min 4 or 5 times a wk.) transition into the active upright position had a positive effect on the body liquids ratio modification in the course of 27-d HDT (-5 degrees). This was concluded from a less pronounced loss in the amount of extracellular liquid and its interstitial component. In addition, another positive result of this manipulation was less, in terms of volume and speed, significant gravity-dependent blood flow toward the lower limbs during 10 minutes of standing test at the end of the experiment as compared with their controls w/o the preventive manipulation.

Anticholinesterase (DFP) toxicity antagonism by chronic donepezil: a potential nerve agent treatment.

Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity.

Acanthopanax senticosus Harms as a prophylactic for MPTP-induced Parkinson's disease in rats.

The aim of this study was to determine whether Acanthopanax senticosus Harms (ASH) offers protection against Parkinson's disease (PD) and its related depressive behaviors in rats administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We examined how ASH affected the MPTP-induced loss of tyrosine hydroxylase (TH)-positive neurons in the midbrain of rats. Extract from the stem bark of ASH prepared with hot water was dissolved in distilled water. Rats were then orally administered ASH (250 mg/kg) once a day for 2 weeks before ASH administration plus an intraperitoneal injection of MPTP (20 mg/kg). The pole test and catalepsy test were used to evaluate the effects of ASH administration on bradykinesia and depressive behaviors in the PD model of rats given MPTP for 2 weeks. Treatment with ASH for 2 weeks resulted in prophylactic effects on MPTP-induced Parkinsonian bradykinesia and catalepsy. Immunohistochemistical analysis using TH antibody showed that ASH provided cytoprotective effects against MPTP-induced loss of dopamine (DA) cells. The present results suggest that it may be possible to use ASH for the prevention of nigral degenerative disorders, e.g., PD with depression, caused by exposure to toxic substances.

Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat.

1. This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg(-1) s.c.). 18 h later, behavioural effects of the group III mGlu receptor agonists L-serine-O-phosphate (L-SOP) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) were examined. 3. In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 microl) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83+/-21 rotations 120 min(-1) (n=8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 microl) inhibited the response to L-SOP (2000 nmol) by 77%. Unilateral injection of L-SOP (250-1000 nmol in 2.5 microl) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 47+/-6 rotations 30 min(-1) (n=6). M-SOP (50 nmol in 2.5 microl) inhibited the response to L-SOP (500 nmol) by 78%. 4. Following i.c.v. injection, L-SOP (2000-2500 nmol in 2.5 microl) or L-AP4 (0.5-100 nmol in 2 microl) produced a dose-dependent reversal of akinesia, attaining a maximum of 45+/-17 (n=8) and 72+/-3 (n=9) arbitrary locomotor units 30 min(-1), respectively. 6. These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.