1J. Comp. Neurol. 2003 Aug 463: 25-43
TitleDifferential distribution of butyrylcholinesterase and acetylcholinesterase in the human thalamus.
AbstractIt has been hypothesized that acetylcholinesterase (ACHE) and butyrylcholinesterase (BuChE) are coregulators of the duration of action of acetylcholine in cholinergic neurotransmission, suggesting that BuChE may also have an important role in the brain. To compare the expression of cholinesterases in the human thalamus, the distributions of BuChE and ACHE activity were studied by using a modified Karnovsky-Roots method. BuChE activity was present mainly in neurons, whereas ACHE activity was present in both neurons and axons. There was intense staining for BuChE or ACHE throughout the thalamus, with some nuclei primarily expressing one or the other cholinesterase. BuChE staining was most intense and widespread in neurons in the anteroventral, mediodorsal, ventral, lateral, and pulvinar thalamic nuclei. ACHE was predominantly expressed in neurons of the anterodorsal, midline, ventral, intralaminar, and reticular nuclei. Many nuclei contained both cholinesterases. Considering the overall patterns of labeling in the thalamus for the two cholinesterases, there were both complementary and overlapping relationships of BuChE and ACHE activity. Neuronal staining in the subthalamic nucleus and hypothalamus was predominantly positive for ACHE activity. The distinct distribution of BuChE activity in neurons in the human thalamus is consistent with an important role for this enzyme in neurotransmission in the human nervous system. Furthermore, BuChE activity, like ACHE activity, is found in certain thalamic nuclei related to cognitive and behavioral functions. Involvement of thalamic nuclei in diseases of the nervous system such as Alzheimer's disease and schizophrenia suggests that BuChE could be a potential target for therapeutic intervention in these disorders.
SCZ Keywordsschizophrenia, schizophrenic
2Pharmacol. Biochem. Behav. 2003 Jul 75: 755-62
TitleZuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.
AbstractAlthough disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated. The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes. In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats. Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) before retrieval testing increased step-through latency during the test session. The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties. This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (ACHE) activity, both of which are known to be important in control of cognitive function. Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) neither affected dopamine (DA) level nor ACHE activity in rat cortex and hippocampus. On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level. These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory. Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic
3Neuropsychopharmacology 2005 Dec 30: 2135-43
TitleCholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice.
AbstractEnhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (ACHE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the ACHE inhibitor (ie physostigmine-0.03, 0.10, or 0.30 mg/kg; donepezil-0.10, 0.30, or 1.00 mg/kg; or galantamine-0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that ACHE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
4Prog. Neuropsychopharmacol. Biol. Psychiatry 2005 Feb 29: 219-32
TitleOn the trail of a cognitive enhancer for the treatment of schizophrenia.
AbstractThe aim of this critical review is to address that the study of cognition and antipsychotics is not always driven by logic and that research into real pro-cognitive drug treatments must be guided by a better understanding of the biochemical mechanisms underlying cognitive processes and deficits. Many studies have established that typical neuroleptic drugs do not improve cognitive impairment. Atypical antipsychotics improve cognition, but the pattern of improvement differs from drug to drug. Diminished cholinergic activity has been associated with memory impairments. Why atypical drugs improve aspects of cognition might lie in their ability to increase dopamine and acetylcholine in the prefrontal cortex. An optimum amount of dopamine activity in the prefrontal cortex is critical for cognitive functioning. Another mechanism is related to procedural learning, and would explain the quality of the practice during repeated evaluations with atypical antipsychotics due to a more balanced blockage of D2 receptors. Laboratory studies have shown that clozapine, ziprasidone, olanzapine, and risperidone all selectively increase acetylcholine release in the prefrontal cortex, whereas this is not true for haloperidol and thioridazine. A few studies have suggested that cholinomimetics or ACHE inhibitors can improve memory functions not only in Alzheimer's disease but also in other pathologies. Some studies support the role of decreased cholinergic activity in the cognitive deficits while others demonstrate that decreased choline acetyltransferase activity is related to deterioration in cognitive performance in schizophrenia. Overall, results suggest the hypothesis that the cholinergic system is involved in the cognitive dysfunctions observed in schizophrenia and that increased cholinergic activity may improve these impairments. Furthermore, a dysfunction of glutamatergic neurotransmission could play a key role in cognitive deficits associated with schizophrenia. Further meta-analysis of various clinical trials in this field is required to account for matters on the grounds of evidence-based medicine.
SCZ Keywordsschizophrenia, schizophrenic
5Recent Pat CNS Drug Discov 2006 Jan 1: 105-11
TitleGalanthamine, a natural product for the treatment of Alzheimer's disease.
Abstract(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive ACHE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approACHEs have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.
SCZ Keywordsschizophrenia, schizophrenic
6Gan To Kagaku Ryoho 2006 Nov 33: 1888-90
Title[A case of a gastric cancer patient who obtained good treatment in spite of a nontreatment decision].
AbstractThe patient was a 57-year-old male who had received schizophrenia and alcoholism treatments for ten years. Hospitalization and release was repeated many times over in the psychiatry department of the hospital up to the present time. He received an upper endoscopy because of a stomach ACHE in May, 2004. He was diagnosed as having gastric cancer (L, post, Type 2, T2 (SS), N2, stage IIIA). Neoadjuvant chemotherapy TS-1+CDDP was begun from the beginning. However, he refused the operation afterwards and we changed the treatment. The chemotherapy was maintained until January, 2005, to enforce seven courses of the treatment and to maintain the long NC for about ten months. Afterwards, he refused the treatment again and did not come to the hospital. After six months, he came to hospital again for pyloric stenosis due to a stomach cancer that developed. We placed a PEG to keep the route for access to the pylorus in August. And we used it to induce the self-expandable metal stent (EMS) to the pylorus. As a result, oral ingestion became possible. He was able to obtain a good QOL for three months until dying thereafter. It is thought that stenting is one of the most effective treatments to correspond to the diversification of the treatment policy.
SCZ Keywordsschizophrenia, schizophrenic
7Handb Exp Pharmacol 2006 -1 -1: 525-44
TitleThe high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice.
AbstractIn cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis. It has previously been shown that HACU is increased by behaviorally and pharmacologically-induced activity of cholinergic neurons in vivo, but the molecular mechanisms of this change in CHT function and regulation have only recently begun to be elucidated. The recent cloning of CHT has led to the generation of new valuable tools, including specific anti-CHT antibodies and a CHT knockout mouse. These new reagents have allowed researchers to investigate the possibility of a presynaptic, CHT-mediated, molecular plasticity mechanism, regulated by and necessary for sustained in vivo cholinergic activity. Studies in various mouse models of cholinergic dysfunction, including acetylcholinesterase (ACHE) transgenic and knockout mice, choline acetyltransferase (ChAT) heterozygote mice, muscarinic (mAChR) and nicotinic (mAChR) receptor knockout mice, as well as CHT knockout and heterozygote mice, have revealed new information about the role of CHT expression and regulation in response to long-term alterations in cholinergic neurotransmission. These mouse models highlight the capacity of CHT to provide for functional compensation in states of cholinergic dysfunction. A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia.
SCZ Keywordsschizophrenia, schizophrenic
8Curr Med Res Opin 2007 Mar 23: 575-83
TitleRivastigmine treatment as an add-on to antipsychotics in patients with schizophrenia and cognitive deficits.
AbstractAlthough new atypical antipsychotic agents have been found to improve overall cognitive function in patients with schizophrenia (SZ), some aspects of memory, attention and executive functions still remain impaired. Acetylcholinesterase (ACHE) inhibitors, such as rivastigmine, have been shown to improve cognition in other disorders, particularly Alzheimer's disease. Dysfunctions in cholinergic systems, especially in the prefrontal cortex, have been identified in SZ, suggesting that cholinesterase inhibitors may be effective in treating cognitive deficits in this disease.
Using a randomized crossover design, we assessed SZ patients with stable symptoms and poor cognitive functioning. Fifty-eight patients with memory deficits, according to subjective complaints or based on clinicians' observations, were assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Subjective Scale to Investigate Cognition in schizophrenia (SSTICS). Only 24 of these subjects met the inclusion criteria. Twenty patients took part in the study (four dropped out). All subjects meeting the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for SZ were maintained on their current antipsychotic medication (18 atypicals and two typicals) and were randomly assigned to treatment with rivastigmine. Dosage was a function of tolerability, beginning at 3 mg/day and progressively increasing to 9 mg/day. Subjects were given the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and 3 and 6 months.
The results revealed no significant improvement in any of the cognitive variables investigated following rivastigmine treatment and symptom severity scores remained unchanged over all recorded time periods.
Rivastigmine treatment did not appear to enhance cognition in SZ patients with important cognitive impairments. This finding needs to be interpreted with care and requires substantiation with larger sample size studies with patients treated with cognitive enhancer for longer periods.
SCZ Keywordsschizophrenia, schizophrenic
9Toxicol. Appl. Pharmacol. 2007 Apr 220: 156-63
TitleThe combination of donepezil and procyclidine protects against soman-induced seizures in rats.
AbstractCurrent treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of the brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (ACHE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6 x LD(50)) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral ACHE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while ACHE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain ACHE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.
SCZ Keywordsschizophrenia, schizophrenic
10Neuropsychopharmacology 2007 Jan 32: 43-53
TitleGalantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors.
AbstractClinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (ACHE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant ACHE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective ACHE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the alpha7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
11J. Pharmacol. Exp. Ther. 2007 Jun 321: 1179-82
TitleThe acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys.
AbstractCholinergic 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.
SCZ Keywordsschizophrenia, schizophrenic
12Br. J. Pharmacol. 2008 Oct 155: 434-40
TitleEffects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat.
AbstractThe beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.
The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The ACHE inhibitor galanthamine was also used alone or in combination with SB-271046.
Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.
These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
13Psychopharmacology (Berl.) 2008 Feb 196: 293-301
TitleGalantamine and donepezil differently affect isolation rearing-induced deficits of prepulse inhibition in mice.
AbstractPrevious studies have shown that alterations in acetylcholine (ACh) receptor subtypes might contribute to cognitive impairment observed in schizophrenia and that choline acetyltransferase activity in the parietal cortex is negatively correlated with the severity of such cognitive impairment. However, clinical data suggest that the acetylcholinesterase (ACHE) inhibitors galantamine and donepezil have different effects on negative and cognitive symptoms in schizophrenia. Prepulse inhibition (PPI) deficits--sensory information-processing deficits observed in schizophrenia--may be useful models for studying the efficacy of ACHE inhibitors as cognitive enhancers.
The present study examined the effects of galantamine and donepezil on PPI deficits induced by an environmental factor and drugs.
In the isolation-rearing model, 3-week-old male ddY mice were housed either in groups of five or six per cage or isolated in cages of the same size for more than 6 weeks. In the drug-induced model, apomorphine 1 mg/kg and MK-801 0.2 mg/kg were administered to 9- to 10-week-old male ddY mice.
In isolation-reared mice, galantamine attenuated PPI deficits, while donepezil did not. Galantamine and donepezil both attenuated PPI deficits induced by apomorphine, but not by MK-801. The galantamine-induced improvements in PPI deficits were not prevented by the nicotinic ACh receptor antagonists mecamylamine and methyllycaconitine.
These observations suggest that galantamine and donepezil have different effects on the environmentally induced PPI deficits and that these observations may be relevant to the different effects of these drugs observed clinically in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
14Zhongguo Zhong Yao Za Zhi 2009 Aug 34: 2018-23
Title[Research advances of Huperzia serrata (Thunb.) Trev].
AbstractQiancengta, a traditional Chinese medicine produced from the whole plant of the club moss Huperzia serrata, has been used for a long history in China for treatment of a number of ailments, including contusions, strains, swellings, schizophrenia, myasthenia gravis and noworganophosphate poisoning. It has become known worldwide as a medicinal plant since Chinese scientists discovered huperzine A from it in the 1980s, which is reversible, potent and selective acetylcholine esterase (ACHE) inhibitors by in vitro and in vivo pharmacological, and produce definite effects in the treatment of Alzheimer's disease. Now, Qiancengta is popular in all over the word for his famous pharmacological actions. For further exploitation this valuable resource under protection of nature environmental, its biological and ecological features, pharmaceutical active ingredients, artificial propagation and in vitro tissue culture, were reviewed, and the sustainable use of Qiancengta natural resource through plant biotechnology was put on the agenda.
SCZ Keywordsschizophrenia, schizophrenic
15Curr Opin Investig Drugs 2010 Jul 11: 740-60
TitleCognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.
AbstractThe limited effect of ACHE inhibitors and NMDA receptor antagonists for the treatment of the cognitive symptoms of Alzheimer's disease has prompted the search for new drugs that are capable not only of treating behavioral symptoms, but also of modifying the disease process. Considerable research efforts have been focused on orthosteric muscarinic M1 functional agonists during the past decade to address both these strategies. Part of this research has included the use of non-human primates as models of cognitive impairment to demonstrate preclinical efficacy. No M1 functional agonist has been successfully registered for the treatment of Alzheimer's disease, mostly because of mechanism-related adverse side effects and marginal cognitive effects. However, the M1 agonist xanomeline exhibited preclinical and clinical efficacy for the treatment of the negative and cognitive symptoms of schizophrenia. These results prompted renewed interest in repositioning compounds such as sabcomeline (Proximagen Group plc) for this indication, as well as developing allosteric muscarinic M1 ligands to improve efficacy while reducing side-effect-related attrition. This review discusses preclinical and clinical data from orthosteric M1 functional agonists, focusing on target validation in primate cognition studies, and provides recommendations for testing a new generation of M1 ligands and compounds with novel mechanisms of action.
SCZ Keywordsschizophrenia, schizophrenic
16Int. J. Neuropsychopharmacol. 2010 Nov 13: 1343-54
TitleGalantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1/2 systems.
AbstractGalantamine, a drug used to treat Alzheimer's disease, inhibits acetylcholinesterase (ACHE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an ACHE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimer's disease.
SCZ Keywordsschizophrenia, schizophrenic
17Am. J. Med. Genet. A 2011 Apr 155A: 805-10
TitlePharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome.
Abstract15q13.3 deletion syndrome (15q13.3DS) is a common recurrent genomic disorder associated with epilepsy, intellectual impairment, aggressive behavior, schizophrenia, and autism. A 39-year-old male presented with 15q13.3DS, epilepsy, intellectual impairment, psychosis, and recurrent episodes of aggressive rage. We hypothesized that the patient's aggressive behavior reflected deficits in ?7 nicotinic cholinergic receptor (NChR)-mediated neurotransmission, arising from haploinsufficiency of the structural gene CHRNA7 due to the deletion. Treatment with the NChR allosteric modulator and acetylcholinesterase (ACHE) inhibitor, galantamine, led to a dramatic decline in the frequency and intensity of rage outbursts, suggesting that enhancement of ?7 NChR function can ameliorate 15q13.3DS-associated rage outbursts.
SCZ Keywordsschizophrenia, schizophrenic
18Pharmacol Rep 2012 -1 64: 191-204
TitleProtective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models.
Abstractschizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (ACHE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain ACHE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.
SCZ Keywordsschizophrenia, schizophrenic
19Pharmacol Rep 2012 -1 64: 191-204
TitleProtective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models.
Abstractschizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (ACHE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain ACHE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.
SCZ Keywordsschizophrenia, schizophrenic
20Neuroscience 2013 Sep 248: 252-60
TitleEffect of maternal deprivation on acetylcholinesterase activity and behavioral changes on the ketamine-induced animal model of schizophrenia.
AbstractMaternal deprivation has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. A growing number of studies demonstrated the importance of childhood experiences in the development of psychosis and schizophrenia in adulthood. Therefore, the present study investigated different behavior responses in rats following maternal deprivation and/or ketamine treatment in adulthood. Male rats were subjected to maternal deprivation for 180 min from postnatal day-01 to postnatal day-10. We evaluated locomotor activity, avoidance task and social interaction of adult male rats deprived or not deprived that were administered with saline or acute subanesthetic doses of ketamine (5, 15 and 25 mg/kg, i.p.). Our results show that only ketamine (25 mg/kg, i.p.) treatment in the adult rats lead to hyperlocomotion but not ketamine (5 and 15 mg/kg) and maternal deprivation alone. However, maternally deprived rats treated with ketamine (5 mg/kg) induced hyperlocomotion. Additionally, ketamine (25 mg/kg) and maternal deprivation alone induced cognitive deficit in the avoidance task. Rats deprived of and treated with ketamine (5, 15 and 25 mg/kg) also lead to memory deficit. Moreover, ketamine (25 mg/kg) and maternal deprivation alone increased latency to start social behavior. However, ketamine (5 mg/kg) and maternal deprivation lead to an increase of latency to start social behavior. Biochemistry data showed that all doses of ketamine and ketamine plus maternal deprivation increased the acetylcholinesterase (ACHE) activity in the prefrontal cortex, hippocampus and striatum. The major doses of ketamine associated with maternal deprivation induced a major increase of ACHE activity. Together, our results suggest that animals subjected to maternal deprivation had an increased risk for schizophrenia-like behavior and cholinergic alteration.
SCZ Keywordsschizophrenia, schizophrenic
21Biomed Res Int 2014 -1 2014: 636574
TitleLong-term effects of maternal deprivation on cholinergic system in rat brain.
AbstractNumerous clinical studies have demonstrated an association between early stressful life events and adult life psychiatric disorders including schizophrenia. In rodents, early life exposure to stressors such as maternal deprivation (MD) produces numerous hormonal, neurochemical, and behavioral changes and is accepted as one of the animal models of schizophrenia. The stress induces acetylcholine (Ach) release in the forebrain and the alterations in cholinergic neurotransmitter system are reported in schizophrenia. The aim of this study was to examine long-term effects of maternal separation on acetylcholinesterase (ACHE) activity in different brain structures and the density of cholinergic fibers in hippocampus and retrosplenial (RS) cortex. Wistar rats were separated from their mothers on the postnatal day (P) 9 for 24 h and sacrificed on P60. Control group of rats was bred under the same conditions, but without MD. Brain regions were collected for ACHE activity measurements and morphometric analysis. Obtained results showed significant decrease of the ACHE activity in cortex and increase in the hippocampus of MD rats. Density of cholinergic fibers was significantly increased in CA1 region of hippocampus and decreased in RS cortex. Our results indicate that MD causes long-term structure specific changes in the cholinergic system.
SCZ Keywordsschizophrenia, schizophrenic
22Acta Neuropsychiatr 2014 Feb 26: 43-50
TitleEvaluation of acetylcholinesterase activity and behavioural alterations induced by ketamine in an animal model of schizophrenia.
AbstractCognitive deficits in schizophrenia play a crucial role in its clinical manifestation and seem to be related to changes in the cholinergic system, specifically the action of acetylcholinesterase (ACHE). Considering this context, the aim of this study was to evaluate the chronic effects of ketamine in the activity of ACHE, as well as in behavioural parameters involving learning and memory.
The ketamine was administered for 7 days. A duration of 24 h after the last injection, the animals were submitted to behavioural tests. The activity of ACHE in prefrontal cortex, hippocampus and striatum was measured at different times after the last injection (1, 3, 6 and 24 h).
The results indicate that ketamine did not affect locomotor activity and stereotypical movements. However, a cognitive deficit was observed in these animals by examining their behaviour in inhibitory avoidance. In addition, an increase in ACHE activity was observed in all structures analysed 1, 3 and 6 h after the last injection. Differently, serum activity of ACHE was similar between groups.
Chronic administration of ketamine in an animal model of schizophrenia generates increased ACHE levels in different brain tissues of rats that lead to cognitive deficits. Therefore, further studies are needed to elucidate the complex mechanisms associated with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
23Neurobiol. Dis. 2014 Jan 61: 55-71
TitleDevelopment of allosteric modulators of GPCRs for treatment of CNS disorders.
AbstractThe discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.
SCZ Keywordsschizophrenia, schizophrenic
24J Enzyme Inhib Med Chem 2015 Dec 30: 995-1001
TitleTacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease.
AbstractA series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of ACHE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hACHE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other ACHE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.
SCZ Keywordsschizophrenia, schizophrenic
25Life Sci. 2015 Jan 121: 65-9
TitleOmega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia.
Abstractschizophrenia is a debilitating neurodevelopmental disorder that is associated with dysfunction in the cholinergic system. Early prevention is a target of treatment to improve long-term outcomes. Therefore, we evaluated the preventive effects of omega-3 fatty acids on ACHE activity in the prefrontal cortex, hippocampus and striatum in an animal model of schizophrenia.
Young Wistar rats (30 days old) were initially treated with omega-3 fatty acids or vehicle alone. Animals received ketamine to induce an animal model of schizophrenia or saline plus omega-3 fatty acids or vehicle alone for 7 consecutive days beginning on day 15. A total of 22 days elapsed between the treatment and intervention. Animals were sacrificed, and brain structures were dissected to evaluate ACHE activity and gene expression.
Our results demonstrate that ketamine increased ACHE activity in these three structures, and omega-3 fatty acids plus ketamine showed lower values for the studied parameters, which indicate a partial preventive mechanism of omega-3 fatty acid supplementation. We observed no effect on ACHE expression. Together, these results indicate that omega-3 fatty acid supplementation effectively reduced ACHE activity in an animal model of schizophrenia in all studied structures. In conclusion, the present study provides evidence that ketamine and omega-3 fatty acids affect the cholinergic system, and this effect may be associated with the physiopathology of schizophrenia. Further studies are required to investigate the mechanisms that are associated with this effect.
SCZ Keywordsschizophrenia, schizophrenic
26Bipolar Disord 2015 May 17: 235-47
TitleClozapine for treatment-resistant bipolar disorder: a systematic review.
AbstractTo evaluate the efficacy and safety of clozapine for treatment-resistant bipolar disorder (TRBD).
A systematic review of randomized controlled studies, open-label prospective studies, and retrospective studies of patients with TRBD was carried out. Interventions included clozapine monotherapy or clozapine combined with other medications. Outcome measures were efficacy and adverse drug reactions (ADRs).
Fifteen clinical trials with a total sample of 1,044 patients met the inclusion criteria. Clozapine monotherapy or clozapine combined with other treatments for TRBD was associated with improvement in: (i) symptoms of mania, depression, rapid cycling, and psychotic symptoms, with many patients with TRBD achieving a remission or response; (ii) the number and duration of hospitalizations, the number of psychotropic co-medications, and the number of hospital visits for somatic reasons for intentional self-harm/overdose; (iii) suicidal ideation and aggressive behavior; and (iv) social functioning. In addition, patients with TRBD showed greater clinical improvement in long-term follow-up when compared with published schizophrenia data. Sedation (12%), constipation (5.0%), sialorrhea (5.2%), weight gain (4%), and body ACHE/pain (2%) were the commonly reported ADRs; however, these symptoms but did not usually require drug discontinuation. The percentage of severe ADRs reported, such as leukopenia (2%), agranulocytosis (0.3%), and seizure (0.5%), appeared to be lower than those reported in the published schizophrenia literature.
The limited current evidence supports the concept that clozapine may be both an effective and a relatively safe medication for TRBD.
SCZ Keywordsschizophrenia, schizophrenic
27Neuropharmacology 2016 Feb 101: 389-400
TitlePositive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.
AbstractAlpha 7 nicotinic acetylcholine receptors (?7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of ?7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced ?7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (ACHE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric ?7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of ?7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of ?7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported.
SCZ Keywordsschizophrenia, schizophrenic
28PLoS ONE 2016 -1 11: e0150574
TitleEffect of Acacia catechu (L.f.) Willd. on Oxidative Stress with Possible Implications in Alleviating Selected Cognitive Disorders.
AbstractIn human body, several categories of degenerative processes are largely determined by free radicals originating in cell. Free radicals are also known to have correlated with a variety of cognitive disorders (CDs) resulting in neuronal injury and eventually to death. Alzheimer's disease (AD) and Parkinson's disease (PD) are such kind of killer CDs that occur due to dysfunction of cholinergic and dopaminergic neurons. Plant parts of Ginkgo biloba, Bacopa monnieri etc. are being used for the treatment of cognitive disorders in several countries. The present study was aimed to explore the detailed antioxidant and anti-cholinesterase activity of Acaciacatechu leaf (ACL) over CDs. Gas chromatography-Mass spectroscopy (GC-MS) analysis and Nuclear Magnetic Resonance (NMR) were employed to identify the bioactive components present in ACL. Furthermore, the extract was evaluated to check the cytotoxic effects of ACL on normal cells. Amongst several antioxidant assays, DPPH assay, hydroxyl radical, nitric oxide radical and hypochlorous acid inhibitory activities were found to be greater in ACL than that of the respective standards while other assays exhibited a moderate or at per inhibitory activity with standards. Total phenolic and flavonoid content were also found to be present in decent amount. In addition, we found, a greater acetylcholinesterase (ACHE) inhibitory activity of ACL when compared to other medicinally important plants, indicating its positive effect over CDs. Forty one bioactive components were explored through GC-MS. Of these, gallic acid, epicatechin, catechin, isoquercitrin etc. were found, which are potent antioxidant and a few of them have anti-neurodegenerative properties. Eventually, ACL was found to be nontoxic and safer to consume. Further studies with animal or human model however, would determine its efficacy as a potential anti-schizophrenic drug.
SCZ Keywordsschizophrenia, schizophrenic