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.

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.

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.

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.

Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain.

Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an anti-apoptotic mechanism and the activation of P1- and P4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. OBJECTIVES: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson's disease. METHODS: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.