Cerebral Metabolic Enhancer Research Articles

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

By restoring mitochondrial function, methylene blue (MB) is an effective neuroprotectant in many neurological disorders (e.g., Parkinson’s and Alzheimer’s diseases). MB has also been proposed as a brain metabolic enhancer because of its action on mitochondrial cytochrome c oxidase. We used in vitro and in vivo approaches to determine how MB affects brain metabolism and hemodynamics. For in vitro, we evaluated the effect of MB on brain mitochondrial function, oxygen consumption, and glucose uptake. For in vivo, we applied neuroimaging and intravenous measurements to determine MB’s effect on glucose uptake, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) under normoxic and hypoxic conditions in rats. MB significantly increases mitochondrial complex I–III activity in isolated mitochondria and enhances oxygen consumption and glucose uptake in HT-22 cells. Using positron emission tomography and magnetic resonance imaging (MRI), we observed significant increases in brain glucose uptake, CBF, and CMRO2 under both normoxic and hypoxic conditions. Further, MRI revealed that MB dramatically increased CBF in the hippocampus and in the cingulate, motor, and frontoparietal cortices, areas of the brain affected by Alzheimer’s and Parkinson’s diseases. Our results suggest that MB can enhance brain metabolism and hemodynamics, and multimetric neuroimaging systems offer a noninvasive, nondestructive way to evaluate treatment efficacy.

Editorial: New drugs for Alzheimer's disease in Japan

Editorial: New drugs for Alzheimer's disease in Japan

Possible Therapeutic Effect of T-794, a Novel Reversible Inhibitor of Monoamine Oxidase-A, on Post-Stroke Emotional Disturbances, Assessed in Animal Models of Depression.

Emotional disturbances, such as lack of motivation or depression, are common after stroke. The drugs mainly used to treat these syndromes in Japan are the cerebral metabolic enhancers whose biochemical and pharmacological profiles are similar to those of antidepressant drugs. In order to examine the possible therapeutic effect of T-794 [(5R)-3-(6-(cyclopropylmethoxy) 2-naphthalenyl)-5-(methoxymethyl) 2-oxazolidone], a new reversible inhibitor of monoamine oxidase (MAO) type A, on those emotional disturbances, its antidepressant activity was compared with those of major cerebral metabolic enhancers in rodents with or without treatment of cerebral ischemia. Oral administration of T-794 potently prevented reserpine-induced ptosis (ED50 = 4.41 mg/kg), akinesia (ED50 = 3.29 mg/kg), and hypothermia (minimum effective dose = 3 mg/kg) in mice. It was at least 3.7, 13.0, and 3.3 times more potent than cerebral metabolic enhancers tested (indeloxazine, bifemelane, amantadine and idebenone) in antagonism of the ptosis, the akinesia, and the hypothermia, respectively. Effect of T-794 was also examined in the behavioral despair test in rats subjected to forebrain ischemia. The ischemia was induced by a combination of bilateral common carotid artery occlusion (15 min) and systemic hypotension (sodium nitroprusside 5 mg/kg, s.c). From 13 d after the surgery, drugs were orally administered twice daily 7 times, and following the last administration rats were assessed for their behavior. T-794 reduced the duration of immobility in the behavioral despair test at 30 mg/kg without affecting spontaneous motor activity, whereas indeloxazine showed no significant effect. Antidepressant-like activity of T-794 was suggested in rodents with as well as those without cerebral ischemia. The results suggest that T-794 may make an important contribution to the treatment of emotional disturbances following stroke.

Electric field distribution of event-related potentials in stroke patients.

Electrical field distributions of event-related potentials (ERP's) were recorded during an auditory "oddball paradigm" and were analyzed in terms of time and space. Fourteen normal subjects and 14 chronic patients were cerebral thrombosis were studied. For the components N1 and P3 of the ERP's to target stimuli, reference-independent measures (latency, global field power, location of maximal or minimal potential, and location of centroids) were determined. Stroke patients displayed P3 abnormalities in latency, amplitude, and electrical field on the scalp. In addition, N1 electrical fields were also abnormal. These ERP abnormalities correlated significantly with the extent of mental function impairment in the stroke patients, and they improved after administration of a cerebral metabolic enhancer (Nefiracetam: DM-9384). The ERP's seemed to be sensitive in indicating the effects of the drug. These data suggest that time-course analysis of the spatial distribution of the ERP electrical field might be useful for evaluation of the extent of mental function impairment and the efficacy of drugs.

Effects of cerebral metabolic enhancers on brain function in rodents

The effects of cerebral metabolic enhancers (indeloxazine, bifemelane, idebenone, and nicergoline) on reserpine-induced hypothermia, the immobility period in forced swimming tests, and passive avoidance learning behavior were compared with the effects of amitriptyline in rodents. Indeloxazine, bifemelane, and amitriptyline antagonized hypothermia in mice given reserpine. Indeloxazine and amitriptyline decreased the immobility period in mice in the forced swimming test in a dose-dependent manner. The latency of step-through in the passive avoidance test in rats was prolonged by administration of indeloxazine but shortened by administration of amitriptyline. Neither idebenone nor nicergoline displayed any pharmacologic action in these tests. The results suggest that indeloxazine possesses an antidepressant activity similar to that of amitriptyline but differs from amitriptyline in its anticholinergic properties and its ability to ameliorate impaired brain function such that of learning behavior. In addition, indeloxazine exhibited broader effects on brain functions than either bifemelane, idebenone, or nicergoline.

Abnormal fatty acid metabolism in patients in hopantenate therapy during clinical episodes

Calcium 4-(2,4-dihydroxy-3,3-dimethylbutyramido)butyrate hemihydrate (hopantenate), a cerebral metabolic enhancer used in Japan since 1978, is a homologue of pantothenic acid. Using mass spectrometry, we found urinary excretion of 4-hydroxydodecanedioic acid, 4-hydroxytetradecanedioic acid and a series of 2-hydroxydicarboxylic acids (C 8–C 14), in addition to a series of odd- and even-numbered dicarboxylic acids (C 5–C 12) and 3-hydroxydicarboxylic acids (C 8–C 14) in patients receiving hopantenate during episodes of Reye's-like syndrome. Our findings suggest that an acute intoxication associated with hopantenate occurs owing to pantothenic acid deficiency or the inhibition of CoA-requiring reactions during stress, i.e. infection, prolonged fasting, or malnutrition.

P-017 - Behavioral effects of OM-853, a cerebral metabolic enhancer, on ambulatory activity, passive and active avoidance responses in mice.

P-017 - Behavioral effects of OM-853, a cerebral metabolic enhancer, on ambulatory activity, passive and active avoidance responses in mice.

14C-Labeling of a New Cerebral Metabolic Enhancer SM-3163.

Both enantiomers of 1- [3- (dimethylamino) propoxy] -1, 5-diphenylpentane citrate (SM-3163), a new cerebral metabolic enhancer, were labeled with 14C at the 1-position of pentyl chain for use in comparative metabolic studies. The synthesis was achieved according to the scheme illustrated in Fig. 2. 14C-Cyanation of 4-phenylbutylbromide (3) with potassium [14C] cyanide (2) followed by the reaction of the resulting nitrile (4) with phenylmagnesium bromide gave the ketone (5) . Reduction of 5 with lithium aluminum hydride produced the racemic alcohol (6) . Optical resolution of 6 by chiral-phase HPLC afforded two optically active alcohols (6a and 6b) . Condensation of 6a and 6b with 3-dimethylaminopropyl chloride and subsequent treatment of the aminoethers (7a and 7b) with citric acid gave (R) -and (S) -SM-3163 (1a and 1b) in the overall yields of 12.5% and 8.2%, respectively.

P-039 - Effect of OM-853, a novel cerebral metabolic enhancer on the spatial learning deficits induced by the basal forebrain (BF)- or the medial septum (MS)-lesioned rats.

P-039 - Effect of OM-853, a novel cerebral metabolic enhancer on the spatial learning deficits induced by the basal forebrain (BF)- or the medial septum (MS)-lesioned rats.

Pharmacological actions of a new TRH analogue, YM-14673, in rats subjected to cerebral ischemia and anoxia

The cerebral protective actions of a new thyrotropin releasing hormone (TRH) analogue, YM-14673, (N α-[[(S)-4-oxo-2-azetidyl-carbonyl]-l- histidyl-L-prolinamide]dihydrate), were compared with those of CDP-choline (cerebral metabolic enhancer) and naloxone in rats rats subjected to unilateral carotid artery ligation and anoxic exposure (Levine rats). Drugs were administered intraperitoneally or orally 20, 80 and 140 min after anoxia. YM-14673 (0.03 to 1 mg/kg i.p. and 0.3 to 10 mg/kg p.o.) decreased the incidence of neurological deficits, such as hemiplegia and convulsion followed by coma and death, for 48 h after ischemia and anoxia. Both the increase in the brain water content and the degeneration of neurons in the cerebral cortex and thalamus were prevented by YM-14673 at a dose of 0.1 mg/kg (i.p.). CDP-choline (400 mg/kg i.p.), which is currently used in the therapy of cerebral vascular diseases, and naloxone (3 mg/kg i.p.) also decreased the incidence of the neurological deficits. These results suggest that YM-14673 protects Levine rats against neurological deficits, presumably by attenuating the development of brain edema and preventing neuronal damage. This compound may be useful in the therapeutic treatment of cerebral vascular diseases.

Pharmacological effects of indeloxazine, a new cerebral activator, on brain functions distinct from other cerebral metabolic enhancers

The effects of indeloxazine hydrochloride [(±)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054], a new cerebral metabolic enhancer, on learned behavior and central monoaminergic function were compared to those of other cerebral metabolic enhancers in animals. Indeloxazine enhanced passive learned behaviour in rats and ameliorated cerebral ischemia-induced learned disturbances in gerbils. Reserpine-induced hypothermia in mice, ponto-genicullo-occipital (PGO) waves in reserpinized cats and caudate spindle activity in cats were reduced by the administration of indeloxazine, suggesting that the drug possesses facilitatory effects on central monoaminergic systems. In contrast, piracetam, calcium-hopantenate. idebenone and bifemelane had no significant effect on learned behavior or central monoaminergic function, with the exception of bifemelane which antagonized reserpine-induced hypothermia. These results are in contrast to the findings that all tested cerebral metabolic enhancers, including indeloxazine, prolonged the survival time of mice subjected to anoxia. The greater effect of indeloxazine to other cerebral metabolic enhancers, in facilitating learned behavior, may be attributable to its broader effects on central monoaminergic systems.

Idebenone improves learning and memory impairment induced by cholinergic or serotonergic dysfunction in rats

The effects of idebenone, a cerebral metabolic enhancer, on learning and memory impairment in two rat models with central cholinergic or serotonergic dysfunction were investigated using positively reinforced learning tasks. A delayed alternation task using a T maze was employed to test the effect of idebenone on short-term memory impairment induced by a cholinergic antagonist, scopolamine. A correct response, defined as a turn toward the arm opposite to that in the forced run, was rewarded with food pellets. Scopolamine (0.2 and 0.5 mg/kg, i.p.) significantly decreased the correct responses to the chance level in the 60-s-delayed alternation task. The scopolamine (0.2 mg/kg, i.p.)-induced impairment of short-term memory was improved by idebenone (3–30 mg/kg, i.p.) or an acetylcholinesterase inhibitor, physostigmine (0.1 and 0.2 mg/kg, i.p.), administered simultaneously. The central serotonergic dysfunction model was produced by giving rats a diet deficient in tryptophan, a precursor of serotonin. The rats fed on a tryptophan-deficient diet (TDD) showed a slower learning process in the operant brightness discrimination task (mult VI15 EXT) than did rats fed on a normal diet. Idebenone (60 mg/kg/day) admixed with the TDD decreased the number of lever-pressing responses emitted during the extinction periods. The percentage of correct responses was significantly higher in the idebenonetreated group than in the control TDD group. These results suggest that idebenone may improve both the impairment of short-term memory induced by a decreased cholinergic activity and the retardation of discrimination learning induced by central serotonergic dysfunction.

Effects of idebenone on memory impairment induced in ischemic and embolization models of cerebrovascular disturbance in rats

Two rat models of memory impairment in passive avoidance learning induced by cerebrovascular disturbance, were established to estimate the effects of a cerebral metabolic enhancer, idebenone. Transient and global cerebral ischemia in rats, produced by 4-vessel occlusion for 200 s immediately after the acquisition trial of passive avoidance learning, shortened the latencies in the retention test trial performed 24 h later. This retrograde amnesia was reversed significantly by idebenone administered orally or intraperitoneally at the doses of 10 and 30 mg/kg before the retention test trial. Idebenone at a dose of 10 mg/kg, given intraperitoneally before or immediately after the ischemia, also markedly inhibited the appearance of amnesia. In the second model, permanent and cerebral hemisphere embolization produced by injecting 2000 microspheres into the internal carotid artery, significantly impaired passive avoidance learning performed 7 days later. The repeated administration of idebenone (30 mg/kg,i.p.), once a day after the embolization, significantly improved the impairment of passive avoidance learning in the embolized rats. Furthermore, physostigmine and arginine-vasopressin as reference compounds improved the impairment of passive avoidance learning in these models. These findings suggest that idebenone ameliorates memory impairment induced by cerebral vascular disturbance in rats.

Cognitive Enhancing Agents: Current Status in the Treatment of Alzheimer's Disease

Extensive recent literature on drugs used to enhance cognitive functioning, reflects the growing social problem of dementia. Many clinical trials have been undertaken with variable success. In most cases the disorder studied has been Alzheimer's disease. The pharmacological approach has been designed to rectify the presumed pathophysiological processes characteristic of the condition. Agents tested include cerebral vasodilators, cerebral metabolic enhancers, nootropics, psychostimulants, neuropeptides and neurotransmitters with a special emphasis on drugs used to enhance cholinergic function. Ethical and practical issues concerning clinical drug trials in dementia will be discussed.

Strategies and new aspects in the pharmacology of drugs for the treatment of senile dementia

AbstractRational therapeutic strategies can be derived only from an understanding of the etiopathogenetic processes leading to dysfunction in the demented brain. Senile dementias (SD) of different origins are associated with biochemical changes in functionally important transmission systems, in energy metabolism, and in synthesis of macromolecules. Much evidence supports a particularly important role of dysfunction in central cholinergic mechanisms. Recent results have furnished encouraging indications that changes in synaptic efficiency and plasticity are integrated to a considerable degree. At present, the pharmacological manipulation of clinical symptoms and impaired functions is the basis for rational strategies in the development of drugs for the treatment of SD. On the basis of present knowledge, the following strategies can be considered: (1) drugs to prevent underlying etiopathogenetic processes (antioxidants, aluminium chelating agents, etc.); (2) enhancers of cerebral neurotransmission; (3) cerebral metabolic enhancers (nootropics and related drugs); (4) modulators of synaptic efficiency and plasticity; (5) nooanaleptics; (6) regulators of cerebral circulation; and (7) symptomatic therapy of associated functional mental disorders. The improvement of neuronal metabolism and synaptic transmission are presently the most important strategies in drug development. Nootropics and related drugs fulfill two aspects in the pharmacotherapy of SD: they are cerebral metabolic enhancers and they improve cerebral synaptic transmission processes. In eight of these functions, the relationship between lipid metabolism and cellular Ca++ homeostasis also may be of special functional importance. For the development of further strategies, more detailed knowledge about the pathogenesis of SD and further experimental modeling of the etiopathogenetic and neuropathological processes underlying SD of different origins are required.

Cerebral activating properties of indeloxazine hydrochloride

The cerebral-activating properties of indeloxazine hydrochloride [(±)-2-[(inden-7-yloxy) methyl]morpholine hydrochloride, YM-08054] were examined in comparison with those of calcium hopantenate (a cerebral metabolic enhancer), dihydroergotoxine (a cerebral vasodilator), viloxazine and amitriptyline (antidepressants). Indeloxazine enhanced the acquisition of learned behavior (passive avoidance, active avoidance and maze learning) and desynchronized the spontaneous EEG in rats. Amnesia in scopelamine-treated rats, disturbances of consciousness in concussed mice and synchronized EEG in rabbits with lesions of the internal capsule were improved by the administration of indeloxazine. Calcium hopantenate and dihydroergotoxine also showed cerebral-activating properties in the majority of behavioral and electroencephalographic paradigms; however neither improved scopolamine-induced amnesia and calcium hopantenate had no effects on learning. Neither viloxazine nor amitriptyline enhanced the acquisition of learned behavior. The results indicate that indeloxazine possesses activating effects on cerebral functions, including learning and the EEG, and that the pharmacological profile of indeloxazine is wider than those of dihydroergotoxine and calcium hopantenate in cerebral-activating activity.

Pharmacology of Dementia

The authors discuss cerebral vasodilators, cerebral metabolic enhancers, nootropics, opioid antagonists, psychostimulants, cholinergic agents, and neuropeptides. Their efficacy in the treatment of dementing illnesses is evaluated.

Therapeutic progress--review XVIII Alzheimer's disease.

Therapeutic progress--review XVIII Alzheimer's disease.

Senile dementia of the Alzheimer type

The etiology, pathophysiology, neurochemistry, diagnosis, clinical presentation, and management of senile dementia of the Alzheimer type (SDAT) are discussed. The etiology of SDAT is unclear. The pathophysiologic changes in the brain tissue of patients with SDAT are quantitative rather than qualitative in comparison to normal age-matched controls. The number of neuritic plaques and neurofibrillary tangles are positively correlated to the severity of clinical symptoms and cognitive impairment. There is overwhelming evidence that SDAT is associated with a loss of cholinergic function. Reduction of choline acetyltransferase activity, a cholinergic marker, has been significantly correlated to the severity of dementia. The diagnosis of SDAT is one of exclusion and is based upon clinical presentation and neurological, psychological, and laboratory testing. The clinical presentation of SDAT involves the progressive deterioration of intellectual capabilities. Management of SDAT primarily involves supportive care and symptom control. Attempts to treat the disease with cerebral vasodilators, metabolic enhancers, and neurotransmitter manipulation have been largely unsuccessful. Drug therapy aimed at reversing or retarding the progression of the disease is not recommended. Behavioral disturbances represent the main indication for drug use in patients with SDAT. The antipsychotic agents are considered the drugs of choice. SDAT remains an enigma. The successes in the treatment of the disease are few, but as more information is gathered on the neurochemical abnormalities involved, there is hope that early detection can prevent the disease or at least slow its progression.

Pharmacotherapy of memory loss in the geriatric patient.

Memory loss is a common problem with advancing age and a prominent symptom in dementia. Categories of drugs used to reverse memory loss and enhance recall are reviewed. Positive results have been observed with cholinergic drugs, acetylcholine precursors, and the newer category of cerebral metabolic enhancers and nootropic agents. Combinations of these classes of drugs are being tried in current research.