Evaluation of betulinic acid effects on pain, memory, anxiety, catalepsy, and oxidative stress in animal model of Parkinson's disease.

Parkinson's disease (PD) is known for motor impairments. Betulinic acid (BA) is a natural compound with antioxidant activity. The present study addresses the question of whether BA affects motor and non-motor dysfunctions and molecular changes in the rat model of PD. The right medial forebrain bundle was lesioned by injection of 6-hydroxydopamine in Male Wistar rats (10-12 weeks old, 270-320 g). Animals were divided into Sham, PD, 3 treated groups with BA (0.5, 5, and 10 mg/kg, IP), and a positive control group received L-dopa (20 mg/kg, P.O) for 7 days. rigidity, anxiety, analgesia, and memory were assessed by bar test, open-field, elevated plus-maze (EPM), tail-flick, and shuttle box. Additionally, the malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, Brain-derived neurotrophic factor (BDNF) and Interleukin 10 (IL10) levels in the whole brain were measured. BA significantly reversed the 6-hydroxydopamine-induced motor and memory complication in the bar test and shuttle box. It modified anxiety-like behavior neither in open-field nor in EPM. It only decreased the time spent in open arms. Moreover, no significant changes were found in the tail-flick between treatment and sham groups. On the other hand, the level of MDA & IL10 were decreased, while the activity of GPx levels of SOD & BDNF in the rats' brains was increased. Our results showed that BA as a free radical scavenger can account for a possible promise as a good therapeutic agent for motor and non-motor complications in PD however further studies may be needed.

Gallic acid improves cognitive, hippocampal long-term potentiation deficits and brain damage induced by chronic cerebral hypoperfusion in rats.

Abstract: Cerebral Hypoperfusion Ischemia (CHI) has important role in neuronal damage and behavioral deficits, including memory and Long-term Potentiation (LTP) impairment. Protective effects of Gallic Acid (GA) on memory, hippocampus LTP and cell viability were examined in permanent bilateral common carotid artery occlusion in rats. Animals were divided into 9 groups: Control (Cont); sham operated (Sho); Cerebral Hypoperfusion Ischemia (CHI); CHI received normal saline (CHI +Veh); CHI treated with different doses gallic acid (50, 100, 200 mg kg(-1) for 5 days before and 5 days after CHI induction, orally); CHI treated with phenytoin (50 mg kg(-1), ip) (CHI+Phe); and sham operated received 100 mg kg(-1), orally (Sho+GA100). CHI was induced by bilateral common carotid artery occlusion (2VO). Behavioral, electrophysiological and histological evaluations were performed. Data were analyzed by one-way and repeated measures ANOVA followed by tukey's post-hoc test. GA improved passive avoidance memory, hippocampal LTP and cell. viability in hippocampus and cortex of ischemic rats significantly (p < 0.01). The results suggest that gallic acid via its antioxidative and free radicals scavenging properties attenuates CHI induced behavioral and electrophysiological deficits and has significant protective effect on brain cell viability. Dose of 100 mg kg(-1) GA has affected the ischemic but not intact rats and its effect was more potent significantly than phenytoin, a routine drug for ischemic subjects.

Protective effects of oral crocin against intracerebroventricular streptozotocin-induced spatial memory deficit and oxidative stress in rats.

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, associated with free radical generation. In this study, we evaluated the effects of crocin on cognitive performance in ICV STZ-lesioned rats (3 mg/kg bilaterally, on day 1 and 3). Crocin (100 mg/kg, p.o.) was administered for 21 consecutive days, starting 1h prior to the first dose of STZ. Cognitive performance was assessed using Morris water maze task while the parameters of oxidative stress assessed, were malondialdehyde (MDA) and total thiol levels besides glutathione peroxidase (GPx) activity. STZ-lesioned rats showed a severe deficit in memory associated with elevated MDA levels, reduced GPx activity and total thiol content. Crocin treatment improved cognitive performance and resulted in a significant reduction in MDA levels and elevation in total thiol content and GPx activity. This study demonstrates that crocin may have beneficial effects in the treatment of neurodegenerative disorders such as Alzheimer's disease.

Forced exercise improves passive avoidance memory in morphine-exposed rats.

The aim of this study was to investigate the effect of short-term forced exercise protocol on passive avoidance retention in morphine-exposed rats. Effects of morphine on acquisition and retrieval of retention have been proven in the avoidance paradigms. Twenty four male Wistar rats weighing 250-300 g were used in this study. Animals were randomly divided into four groups including: (1) non-morphine-exposed without exercise (nA.nE) (2) non-morphine-exposed with exercise (nA.E) (3) morphine-exposed without exercise (A.nE) and (4) morphine-exposed with exercise (A.E). Rats ran as forced exercise on the motorized treadmill 1 h daily for ten days. Morphine-exposed animals received intraperitoneal morphine during first 5 days of the exercise period and their dependence to morphine was confirmed by naloxane admistration (10 mg kg(-1), i.p.) and withdrawal test. After 10 days of forced exercise, step down latency was tested and Inflexion Ratio (IR) was evaluated in each rat. Baseline step down latencies before any morphine exposing or exercise have shown no significant alteration in all groups. Inflexion Ratio (IR) ofnA.E group has increased significantly (p<0.001) at 1, 3, 7 and 14 days after receiving shock (learning) compared to nA.nE and A.E groups. Our data showed that short-term forced exercise on treadmill improved retention in both morphine-exposed and non morphine-exposed rats at least up to 7 days and more than 14 days, respectively. Alteration in retention between exercised groups may attribute the release of adrenal stress hormones such as epinephrine and corticosterone because of the emotional arousal.

The effect of peripheral administration of growth hormone on AD-like cognitive deficiency in NBM-lesioned rats.

This study aimed to evaluate the peripheral administration of growth hormone (GH) on AD-like cognitive deficiency in NBM-lesioned rats induced by ibotenic acid (5 microg/microl, in each side). Forty-eight male Wistar rats (20-24 months old; weighing 330+/-30 g) randomly divided into six groups (n=8). The groups include control group, which were intact rats; n-L+GH group: non-lesioned rats with GH treatment (1mg/kg, 9.00 am, for 10 consecutive days); n-L+Veh group: non-lesioned rats with vehicle treatment; L group: NBM-lesioned rats; L+GH group: NBM-lesioned rats with GH treatment and L+Veh group: NBM-lesioned rats with same volume of vehicle treatment. Peripheral administration of GH in control had no effect on learning and memory, while in L+GH group produced a significant enhancement in spatial learning and memory comparing to L and L+Veh groups. The percent of time spent in goal quarter during probe trial has decreased significantly in L and L+Veh groups compared to n-L groups. While it has increased significantly in L+GH group compared to L and L+Veh groups. No significant difference in percent of time spent was seen between the control and n-L groups. The GH has known as a mediate that effect through IGF-1. As the IGF-1 itself is earlier shown to improve cognitive function it is likely that the observed effect of GH is mediated through release of IGF-1 from peripheral tissue into the circulation for further transport across the BBB. This mechanism may result in the improvement of learning and memory in rats with NBM lesion.

Effect of intrahippocampal injection of aluminum on active avoidance learning in adult male rats.

Aim of this research was to study the effect of intrahippocampal injection of different doses of AlCl3 in adult male rats on active avoidance learning. Thirty five adult male Wistar rats (250-300 g) were used into five groups: (1) Control, (2) Test-I received daily 1 microL AlCl3 1%, pH = 7.2, 3); Test-II received daily 1 microL AlCl3 0.5%, pH = 3.4, 4); Sham-I received daily 1 microL aCSF, pH = 7.2, 5); Sham-II received daily 1 microL aCSF, pH = 3.4. All rats in test and sham groups treated 10 min before training. Animals were anaesthetized with ketamine HCl/xylazine (90/10 mg kg(-1) b.wt.(-1), i.p.) and underwent a stereotaxic surgery for implant of two stainless steel guide cannula into the hippocampus bilaterally. Every day 10 min after above treatments all rats were used to assess the spatial learning performing using Y-maze. Criterion Correct Response (CCR) was 90% in last session of training. There were no significant differences between training sessions to receiving CCR in control, Sham-I and Sham-II groups. Cognition in animals received AlCl3 1%, pH = 7.2 was impaired significantly with compare to other groups (*p<0.0001). Present results show that intrahippocampal injection of AlCl3 1%, causes active avoidance learning impairment significantly. The exact mechanism of Al3 effect on brain and cognition is remains unknown.

Preventive effects of soy meal (+/- isoflavone) on spatial cognitive deficiency and body weight in an ovariectomized animal model of Parkinson's disease.

The aim of the present study was to investigate the preventive effect of 4 weeks soy meal (+/- isoflavone) on post-menopausal cognitive deficiency and body weight alteration in ovariectomized (OVX)-6-hydroxy dopamine (6-OHDA)-induced animal model of Parkinson's Disease (PD) which mimics status in menopause women. Female Wistar rats (250-300 g, 5-6 months old) were divided into 2 main groups. (1) Control; (2) OVX; included 5 subgroups that were pre-treated with 10 or 20 g soy with isoflavone in 30 g daily diet (10 and 20 groups, respectively), 10 or 20 g soy without isoflavone in 30 g daily diet (-10 and -20 groups, respectively) and 0 g soy (sham treated group) during 4 weeks after OVX. To induce animal model ofPD in main second group (OVX rats) the substantia nigra pars compacta (SNpc) was lesioned by 6-hydroxydopamine (6-OHDA) (8 microg kg(-1) 4 microL(-1) normal saline contains 0.1% ascorbate). All animals were trained in Morris water maze for evaluating the spatial learning and memory. The results indicated that pre-treatment of Parkinsonian rats with different doses of dietary soy meal (+/- isoflavone) improved the spatial learning and memory and prevents increasing the body weight after menopause significantly. Our data show that, long-duration dietary soy meal may have the potential neuroprotective effect against post-menopausal cognitive deficiency induced by degeneration of nigrostriatal dopaminergic system and constant body weight during post-menopausal life cycle.

The effect of intra-hippocampal injection of growth hormone on spatial learning and memory in animal model of Alzheimer's disease.

The aim of this study was to evaluate the effect of intra-hippocampal injection of Growth Hormone (GH) on impaired spatial cognition in rats with Alzheimer's Disease (AD). Growth hormone replacement therapy leading to improved cognition and well-being has mainly been carried in GH-deficient patients. Nevertheless, relatively only a few studies have investigated the function of GH in the brain. Aged Wistar male rats (350-400 g, 18-20 months old) were randomly divided into 6 groups (7 in each): Control (healthy aged); L; L + Veh; L + GH10; L + GH20 and L + GH40. Rats with AD-like cognitive deficiency was induced by injection of ibotenic acid into Nucleus Basalis of Meynert (NBM) bilaterally (5 microg 0.5 microL(-1), each side). A guide cannula was implanted in the right hippocampus under stereotaxic surgery for injection of human recombinant GH (10, 20 and 40 microg 2 microL(-1), during 5 min, twice daily, 9:00 am and 3:00 pm, for 7 days). All rats were trained in Morris water maze to evaluate the spatial learning and memory. Escape latency, traveled distance to find hidden platform and percent time spent in gaol qudrant did not differ between L and L + Veh groups, while latency and distance were reduced significantly. But percent time spent in gaol quadrant (without hidden platform) was increased significantly in NBM-lesioned rats treated with GH (L + GH groups) dose dependently to compare with vehicle treated group. These results suggest that intra-hippocampal injection of GH to aged rats with dementia type of AD (with NBM lesioned) could improve spatial cognition.

Postmenopausal effects of intrastriatal estrogen on catalepsy and pallidal electroencephalogram in an animal model of Parkinson's disease.

The main objective was to test the preventive and treatment effects of central injection of estrogen (ES) on muscular rigidity and pallidal EEG in menopausal rats' model of Parkinson's disease (PD). We hypothesized that intrastriatal pretreatment and post-lesion treatment by estrogen improve the pallidal local EEG and muscular stiffness in animal model of menopause with PD. Forty-eight female Wistar rats (300-350 g) were ovariectomized (OVX) and divided into two main groups: Non-pretreated subgroups; sham (S), lesioned (L), post-lesion treated (LT) and pretreated subgroups; pretreated (Pt), pretreated and then lesioned (PtL), pretreated and post-lesion treated (PtLT). Pallidal local EEG was recorded by a bipolar recording electrode and muscle stiffness was scored by Dekundy's test in freely moving rats. Muscle stiffness and pallidal local EEG were indicated as main outcome measures. In pretreated group the local pallidal EEG was decreased in sham-operated rats compared with non-pretreated group (P<0.01), and SNc lesioning decreased EEG in the non-pretreated (P<0.01), while it increased the EEG in the pretreated group (P<0.01). In both groups administration of ES restore the EEG to the respective sham-operated group (P<0.01). Regarding muscle stiffness, it increased after SNc lesioning in both pretreated and non-pretreated groups and ES administration decreased the rigidity significantly (P<0.05, P<0.001 respectively). However, the lesion-induced rigidity in pretreated groups was significantly less than non-pretreated groups (P<0.05). Because of its modulatory effect estrogen may protect dopaminergic neurons from injury and may interfere with the uptake of 6-hydroxydopamine (6-OHDA) into the nigral dopaminergic neurons or alter dopamine release and uptake in remaining neurons.

The neuroprotective effects of progesterone on experimental diabetic neuropathy in rats.

This study was conducted to investigate the neuroprotective effects of progesterone (PROG) on electrophysiological and histomorphometrical alternation in STZ-induced diabetic neuropathy starting from 4 weeks after the diabetic induction. Thirty adult male Sprague-Dawley rats were randomly divided into 3 groups (with 10 rats in each), control (nondiabetic), untreated diabetic and diabetic PROG-treated. Diabetes was induced in adult male rats by a single dose injection of streptozotocin (STZ, 55 mg kg(-1), i.p.). In the PROG-treated group, 4 weeks after induce of diabetes; rats were treated with PROG (8 mg kg(-1), i.p., every two days) for 6 weeks. Diabetic rats showed a significant reduction in motor nerve conduction velocity (MNCV), mean myelinated fibers (MFs) diameter, axon diameter and myelin sheath thickness in the sciatic nerve after 6 weeks. In the untreated diabetic group endoneurial edema was observed in sciatic nerve and the numbers of MFs with infolding into the axoplasm, irregularity of fibers, myelin sheath with unclear boundaries and alteration in myelin compaction were also increased. Long-term treatment with PROG increased MNCV significantly and prevented all these abnormalities in treated diabetic rats. Our findings indicated that PROG as a therapeutic approach can protect neurophysiologic and histomorphologic alterations induced by peripheral diabetic neuropathy.

Apple cider vinegar attenuates lipid profile in normal and diabetic rats.

In this study, the effect of apple cider vinegar on Fasting Blood Glucose (FBG), glycated haemoglobin (HbA1c) and lipid profile in normal and diabetic rats was investigated. Diabetes was induced in male Wistar rats (300+/-30 g) by the intraperitoneal injection of streptozotocin (60 mg kg(-1) of body weight). Both normal and diabetic animals were fed with standard animal food containing apple cider vinegar (6% w/w) for 4 weeks. Fasting blood glucose did not change, while HbA1c significantly decreased by apple cider vinegar in diabetic group (p<0.05). In normal rats fed with vinegar, significant reduction of low density lipoprotein-cholesterol (LDL-c) (p<0.005) and significant increase of high density lipoprotein-cholesterol (HDL-c) levels (p<0.005) were observed. Apple cider vinegar also reduced serum triglyceride (TG) levels (p<0.005) and increased HDL-c (p<0.005) in diabetic animals. These results indicate that apple cider vinegar improved the serum lipid profile in normal and diabetic rats by decreasing serum TG, LDL-c and increasing serum HDL-c and may be of great value in managing the diabetic complications.

Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice.

Mice carrying mutated human APPswe and PS1 (A246E) transgenes (A/P mice) show age-dependent memory impairment in hippocampus-dependent tasks. Moreover, the mice show normal learning in the water maze within a day but impairment across days. We recorded LTP in a slice preparation (CA1) and in chronically implanted animals (dentate gyrus, or DG) at 17-18 months of age. The genotypes did not differ in the basal synaptic transmission. Also, LTP induction and its maintenance over 60 min did not differ between A/P and control mice. However, the fEPSP enhancement in vivo decayed to 77% of its maximum in 24 h in A/P mice while remaining at 96% in control mice. The time course of the LTP decay in the A/P mice corresponds to their behavioral impairment and indicates that Abeta accumulation in the dentate gyrus may interfere with the signal transduction pathways responsible for memory consolidation.