Deferiprone ameliorates memory impairment in Scopolamine-treated rats: The impact of its iron-chelating effect on ß-amyloid disposition.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive and memory problems. Scopolamine (SCOP) is a natural anticholinergic drug that was proven to cause memory impairment in rats. Chelating agents are potential neuroprotective and memory enhancing agents as they can trap iron that enters in pathological deposition of ß-amyloid (Aß) which is a hallmark in AD and memory disorders. This study investigated the potential neuroprotective and memory enhancing effects of the iron chelating drug, Deferiprone. Three doses (5, 10, and 20 mg/kg) were administered to rats treated with SCOP (1.14 mg/kg/day). Systemic administration of SCOP for seven days caused memory impairment which manifested as decreased time spent in platform quadrant in Morris water maze test, decreased retention latencies in passive avoidance test, and increased acetylcholinesterase (AChE) activity, Aß, and free iron deposition. It was observed that pretreatment with Deferiprone increased platform quadrant time in Morris water maze and increased retention latencies in the passive avoidance test. It also attenuated the increase in AChE activity and decreased Aß and iron deposition. Overall, Deferiprone (10 mg/kg) was determined as the most effective dose. Therefore, this study suggests neuroprotective and memory enhancing effects for Deferiprone in SCOP-treated rats which might be attributed to its iron chelating action and anti-oxidative effect.

Ameliorative Effects of α-Tocopherol and/or Coenzyme Q10 on Phenytoin-Induced Cognitive Impairment in Rats: Role of VEGF and BDNF-TrkB-CREB Pathway.

Phenytoin is one of the most well-known antiepileptic drugs that cause cognitive impairment which is closely related to cAMP response element-binding protein (CREB) brain-derived neurotrophic factor (BDNF) signaling pathway. Moreover, vascular endothelial growth factor (VEGF), an endothelial growth factor, has a documented role in neurogenesis and neuronal survival and cognitive impairment. Therefore, this study aimed to investigate the influence of powerful antioxidants: α-Toc and CoQ10 alone or combined in the preservation of brain tissues and the maintenance of memory formation in phenytoin-induced cognitive impairment in rats. The following behavioral test novel object recognition and elevated plus maze were assessed after 14 days of treatment. Moreover, VEGF, BDNF, TrkB, and CREB gene expression levels in the hippocampus and prefrontal cortex were estimated using RT-PCR. Both α-Toc and CoQ10 alone or combined with phenytoin showed improvement in behavioral tests compared to phenytoin. Mechanistically, α-Toc and/or CoQ10 decreases the VEGF mRNA expression, while increases BDNF-TrKB-CREB mRNA levels in hippocampus and cortex of phenytoin-treated rats. Collectively, α-Toc and/or CoQ10 alleviated the phenytoin-induced cognitive impairment through suppressing oxidative damage. The underlying molecular mechanism of the treating compounds is related to the VEGF and enhancing BDNF-TrkB-CREB signaling pathway. Our study indicated the usefulness α-Toc or CoQ10 as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.

Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1/NRF2 signaling pathways.

Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2-related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.

Effects of genistein on pentylenetetrazole-induced behavioral and neurochemical deficits in ovariectomized rats.

Estrogenic compounds have been documented in literature to exert neuroprotective effects. This study investigated the potential neuroprotective effect of genistein; a phytoestrogen at doses of 5, 10, 20, and 40 mg/kg p.o. in ovariectomized rats challenged with pentylenetetrazole (PTZ) 90 mg/kg i.p. Systemic acute administration of PTZ induced seizures, increased oxidative stress, and caused apoptosis and histological abnormalities. Pretreatment with genistein delayed seizure onset, reduced the seizure duration, improved oxidative stress profile, decreased estrogen receptor expression, reduced apoptosis, and improved the histopathological pattern. Overall, the genistein doses (10 and 20 mg/kg) showed the strongest protective effects. In conclusion, the current study suggests that genistein exhibits neuroprotective effects against PTZ-induced seizures. Such effects might be attributed to its estrogenic, antioxidant, and/or anti-apoptotic properties.

Anti-acetylcholinesterase activity of essential oils and their major constituents from four Ocimum species.

Ocimum is a genus of considerable importance in traditional medicine worldwide. The goal of this study was to examine the anti-acetylcholinesterase activity of Ocimum essential oils and to correlate the activity with their chemical profiles using a metabolome based GC-MS approach coupled to chemometrics. Further, molecular docking was adopted to rationalize the activity of some essential oil isolates. Essential oil prepared from the four species O. basilicum, O. africanum, O. americanum, and O. minimum exhibited significant anti-acetylcholinesterase activity with (IC50 0.22, 0.175, 0.57 and 0.152 mg/mL, respectively) comparable to that of physostigmine (IC50 0.27 mg/mL). The phenylpropanoids (i.e. estragole) constituted the most dominant chemical group in O. basilicum (sweet basil) and O. minimum, whereas camphor (a ketone) was the most abundant in O. africanum and O. americanum. Supervised and unsupervised multivariate data analyses clearly separated O. africanum and O. americanum from other accessions, with estragole, camphor and, to less extent, ß-linalool contributing to species segregation. Estragole was found the most active AchE inhibitor (IC50 0.337 µM) followed by cineole (IC50 2.27 µM), camphor (IC50 21.43 µM) and eugenol (IC50 40.32 µM). Molecular docking revealed that these compounds bind to key amino acids in the catalytic domain of AchE, similar to standard drugs.

In vivo anti-inflammatory activity of caffeoylquinic acid derivatives from Solidago virgaurea in rats.

CONTEXT: Solidago virgaurea L. (Asteraceae) is traditionally used as an anti-inflammatory for the treatment of various symptoms including cystitis. However, little is known concerning the constituents responsible for this activity and the mechanism of their action. OBJECTIVE: To assess the anti-inflammatory activity of the phenolic-rich fraction of S. virgaurea aerial parts in rats, isolate and assess the activity of the major compounds present. MATERIALS AND METHODS: An HPLC method was developed for the analysis of the phenolic-rich fraction (EtFr). The in vivo anti-inflammatory activity of the EtFr and four isolated compounds (at 25 and 50 mg/kg) were assessed in adult male rats using the carrageenan-induced rat paw oedema model. The levels of the pro-inflammatory cytokines (TNF-α and IL-1ß) were measured using ELISA. RESULTS: 3,5-O-Dicaffeoylquinic acid (1), 3,4-O-dicaffeoylquinic acid (2), 3,4,5-O-tricaffeoylquinic acid (3) and 4,5-O-dicaffeoylquinic acid (4) were isolated from EtFr. Compound 3 (50 mg/kg) showed a highly significant activity in inhibiting the oedema volume after 3 h (88% of the activity of indomethacin at 10 mg/kg). The EtFr and the isolated compounds largely inhibited the excessive production of the inflammatory mediators TNF-α and IL-1ß. DISCUSSION AND CONCLUSION: This is the first report of 3,4,5-tri-O-caffeoylquinic acid (3) in Solidago species. The tricaffeoylquinic acid (3) showed a significantly higher activity than the other three dicaffeoylquinic acids (1, 2, 4) and indomethacin in reduction of TNF-α and IL-1ß concentrations (8.44 ± 0.62 and 5.83 ± 0.57 pg/mL compared to 12.60 ± 1.30 and 52.91 ± 5.20 pg/mL induced by indomethacin, respectively).

Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum.

Huntington's disease (HD) is a neurodegenerative disorder, characterized by selective atrophy in the striatum, particularly the medium spiny GABAergic efferent neurons. This results in striatal sensorimotor gating deficits. Systemic administration of 3-nitropropionic acid (3-NPA) produces selective lesions mimicking those of HD. Males were found to be more susceptible to 3-NPA-induced neurotoxicity than females, suggesting neuroprotective effects of estrogens. Phytoestrogens, including genistein, are good estrogenic alternatives that keep their beneficial effects on non-reproductive organs and lack the potential hazardous side effects. The current study was designed to investigate the potential beneficial effects of genistein in 3-NPA-induced HD in ovariectomized rats. Results showed that 3-NPA (20 mg/kg) administration caused significant disruption of the rats' locomotor activity and prepulse inhibition. In addition, it decreased striatal ATP levels and increased oxidative stress, inflammatory and apoptotic markers with striatal focal hemorrhage and gliosis. Pretreatment with 17ß-estradiol (2.5 mg/kg) or genistein (20 mg/kg) led to a significant improvement of behavioral parameters, increased ATP production, decreased oxidative stress, attenuated inflammation and apoptosis. Therefore, this study suggests potential neuroprotective effects of genistein in ovariectomized rats challenged with 3-NPA.

The effect of pomegranate fruit extract on testosterone-induced BPH in rats.

BACKGROUND: Benign prostatic hyperplasia (BPH) affects many men after the age of 50 years. Inflammation and oxidative stress along with apoptotic changes are thought to play an important role in the pathology of BPH. Pomegranate contains a variety of polyphenolic compounds that have been studied in a medley of diseases for their anti-oxidant, anti-inflammatory and pro-apoptotic properties. Therefore, this study examined the effect of Pomegranate Fruit Extract (PFE) on the development of BPH using a testosterone-induced BPH model in rats. METHODS: A total of 48 rats were randomly divided into six groups of eight, one group served as the control, BPH was induced by testosterone 3 mg/kg S.C. daily in four groups, three of them received PFE by oral gavage daily at doses of 25, 50, and 100 mg/kg respectively, while one group received PFE at a dose of 50 mg/kg without induction of BPH. RESULTS: PFE at a dose of 100 mg/kg was the most effective in decreasing testosterone-induced increase in prostate weight, prostate weight/body weight ratio, and PAP levels by 30.8%, 55%, and 68% respectively and in preventing the accompanying histological changes. In the BPH model, testosterone significantly decreased GSH, SOD, and CAT to 0.45, 0.64, and 0.88 of the control group values respectively, and significantly increased MDA by >6-fold. In combination with testosterone, PFE dosed at 100 mg/kg significantly increased GSH, SOD, and CAT to 0.83, 0.92, and 0.93 of the control group values respectively, whereas MDA was significantly decreased by 72% compared with the testosterone treated group. In addition to this, at the range of doses studied, PFE lowered COX-II, iNOS, Ki-67 expression, and increased apoptotic index. CONCLUSION: The current findings elucidate the effectiveness of PFE in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its anti-oxidant, anti-inflammatory, and pro-apoptotic properties.

Prepulse inhibition (PPI) disrupting effects of Glycyrrhiza glabra extract in mice: a possible role of monoamines.

Liquorice extract was reported to have nootropic and/or antiamnestic effects. Prepulse inhibition (PPI) of startle response is a multimodal, cross-species phenomenon used as a measure of sensorimotor gating. Previous studies indicated that liquorice/its constituents augmented mouse brain monoamine levels. Increased brain monoamines' transmission was suggested to underlie PPI disruption. However, the effect of antiamnestic dose(s) of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. The effect of administration of the antiamnestic dose of the extract (150 mg/kg for 7 days) was tested on PPI of acoustic startle response in mice. It resulted in PPI disruption and therefore its effect on monoamines' levels was investigated in a number of mouse brain areas involved in PPI response mediation. Results demonstrated that the extract antiamnestic dose augmented cortical, hippocampal and striatal monoamine levels. It was therefore concluded that liquorice extract (150 mg/kg)-induced PPI deficit was mediated through augmenting monoaminergic transmission in the cortex, hippocampus and striatum. These findings can be further investigated in experimental models for autism, psychosis and Huntington's disease to decide the safety of using liquorice extract in ameliorating memory disturbance in disorders manifesting PPI deficit.

Role of the phytoestrogenic, pro-apoptotic and anti-oxidative properties of silymarin in inhibiting experimental benign prostatic hyperplasia in rats.

Androgen and estrogen play an important role in the pathogenesis of benign prostatic hyperplasia (BPH). Estrogen exerts its action through two distinct estrogen receptors (ERs) either ER-α or ER-ß. The phytoestrogenic property of silymarin (SIL) has been previously characterized. Thus, this study examined the protective effect of SIL against testosterone-induced BPH in rats. In an initial dose-response study, SIL in a dose of 50mg/kg was the most effective in preventing the rise in prostate weight, prostate weight/body weight ratio and histopathologic changes induced by testosterone. Testosterone significantly decreased ER-ß and increased ER-α and AR expressions as compared to the control group and these effects were significantly ameliorated by SIL. Furthermore, SIL significantly protected against testosterone-provoked decline in mRNA expression of P21(WAF1/Cip1) and Bax/Bcl-xl ratio as well as caspase-3 activity. SIL minimized the number of proliferating cell nuclear antigen (PCNA) positive cells as compared to testosterone-treated group. Moreover, SIL significantly blunted the inducible NF-κB expression and restored the oxidative status to within normal values in the prostatic tissues. Collectively these findings elucidate the effectiveness of SIL in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its phytoestrogenic, pro-apoptotic and anti-oxidative properties.

Potential neuroprotective effects of hesperidin on 3-nitropropionic acid-induced neurotoxicity in rats.

Huntington's disease (HD) is a progressive neurodegenerative disorder with a spectrum of cognitive, behavioral, and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes, primarily manifested as prepulse inhibition (PPI) deficit of acoustic startle stimuli, and selective striatal lesions in rats and primates mimicking those in HD. The implications of nitric oxide in a variety of neurodegenerative diseases attract attention to study the possible role of flavonoids in interaction with nitric oxide pathways involved in HD. The present study investigates the potential effect of hesperidin, a flavanone group member, on 3-NP-induced behavioral, neurochemical, histopathological and cellular changes. Systemic administration of 3-NP to rats for 5 days (20 mg/kg) caused reduction of locomotor activity by days 2 and 5, 55% deficit of PPI response, elevation of cortical, striatal and hippocampal malondialdehyde (MDA) levels by 63%, 41% and 56%, reduction of respective catalase activity by 50%. Immunohistochemical staining of cortices, striata and hippocampi showed patches of iNOS positive cells. Electron microscopic ultrastructural examination showed marked mitochondrial swelling, perivascular edema and shrunken nerve cells. Pretreatment with hesperidin (100 mg/kg) ahead of 3-NP prevented any changes of locomotor activity or PPI response, slightly increased cortical, striatal and hippocampal MDA levels by 10% and reduced respective catalase activity by 22%, 20% and 5%. Only few iNOS positive cells were detected in sections from rats pretreated with hesperidin which also reduced cellular abnormalities induced by 3-NP. This study suggests a potential neuroprotective role of hesperidin against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be referred to its antioxidant and anti-inflammatory activities.

The effect of Ginkgo biloba extract on 3-nitropropionic acid-induced neurotoxicity in rats.

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase enzyme (SDH), induces neurodegeneration similar to that observed in Huntington's disease (HD). Reduction of prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity, bilateral striatal lesions as well as brain oxidative stress are major features of HD. The present study was designed to investigate neuroprotective effect of Ginkgo biloba extract (EGb 761) on 3-NP induced neurobehavioral changes and striatal lesions. Rats administered 3-NP (20mg/kg, s.c.) for five consecutive days exhibited PPI deficits and locomotor hypoactivity whereas, pretreatment of animals with EGb 761 (100mg/kg, i.p. for 15 days) ahead of and during the induction of HD by 3-NP (20mg/kg for 5 days starting at day 8) ameliorated 3-NP-induced neurobehavioral deficits. Administration of 3-NP increased the level of striatal malondialdehyde (MDA). This effect was prevented in animals pre-treated with EGb 761. Changes in the level of apoptotic regulatory gene expressions, following 3-NP treatment, were demonstrated as both an up-regulation and a down-regulation of the expression levels of striatal Bax and Bcl-xl genes, respectively. In addition, an up-regulation of the expression level of striatal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also observed. Pre-treatment with EGb 761 caused a down-regulation in striatal GAPDH and Bax together with an up-regulation of striatal Bcl-xl expression level as compared to the 3-NP treated group. Histochemical examination of striatal tissue showed that EGb 761 significantly prevented 3-NP induced inhibition of SDH activity. Histopathological examination further affirmed the neuroprotective effect of EGb 761 against 3-NP toxicity. Taken together, these results suggest that EGb 761 has a neuroprotective role in the current HD paradigm, which may be related to improvement of energy metabolism, antioxidant properties and antiapoptotic effects.

Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

Proapoptotic and prepulse inhibition (PPI) disrupting effects of Hypericum perforatum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. AIM OF THE STUDY: Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. MATERIALS AND METHODS: The effects of acute (500 mg/kg) and chronic (200mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. RESULTS: Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. CONCLUSIONS: The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.