Stimulatory Effect of the D2 Antagonist Sulpiride on Glucose Utilization in Dopaminergic Regions of Rat Brain

Local cerebral glucose utilization (LCGU) was measured, using the quantitative autoradiographic [14C]2-deoxy-D-glucose method, in 56 brain regions of 3-month-old, awake Fischer-344 rats, after intraperitoneal administration of sulpiride (SULP) 100 mg/kg. SULP, an "atypical" neuroleptic, is a selective antagonist of D2 dopamine receptors. LCGU was reduced in a few nondopaminergic regions at 1 h after drug administration. Thereafter, SULP progressively elevated LCGU in many other regions. At 3 h, LCGU was elevated in 23% of the regions examined, most of which are related to the CNS dopaminergic system (caudate-putamen, nucleus accumbens, olfactory tubercle, lateral habenula, median eminence, paraventricular hypothalamic nucleus). Increases of LCGU were observed also in the suprachiasmatic nucleus, lateral geniculate, and inferior olive. These effects of SULP on LCGU differ from the effects of the "typical" neuroleptic haloperidol, which produces widespread decreases in LCGU in the rat brain. Selective actions on different subpopulations of dopamine receptors may explain the different effects of the two neuroleptics on brain metabolism, which correspond to their different clinical and behavioral actions.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Effect of thyrotropin-releasing hormone (TRH) on local cerebral glucose utilization, by the autoradiographic 2-deoxy[14C]glucose method, in conscious and pentobarbitalized rats

Effects of TRH and pentobarbital alone, and in combination, on local cerebral glucose utilization of rats were studied by the autoradiographic 2-deoxy[14C]glucose method. TRH (5 mg/kg i.v.) reduced the rate of cerebral glucose utilization slightly in the whole brain. Locally, significant depression was observed in the following structures: frontal and visual cortices, hippocampus Ammon's horn and dentate gyrus, medial and lateral geniculate bodies, nucleus accumbens, caudate-putamen, substantia nigra, pontine gray matter, superior colliculus, superior olivary nucleus, vestibular nucleus, lateral lemniscus and cerebellar cortex. Pentobarbital (30 mg/kg i.v.) produced a marked and diffuse reduction in the rate of glucose utilization throughout the brain. TRH given 15 min after the administration of pentobarbital markedly shortened the pentobarbital sleeping time and caused some reversal of the depression in local cerebral glucose utilization produced by pentobarbital. These effects were almost completely abolished by pretreatment with intracerebroventricular injection of atropine methyl bromide (20 microgram/rat). These results indicate that although TRH acts to cause a reduction in the rate of cerebral glucose utilization, it reverses the depression induced by pentobarbital, via a cholinergic mechanism, in a number of structures, some of which are related to monoaminergic systems and the reticulo-thalamo-cortical activating system.     

Effects of Hyperprolactinemia on Plasma Prolactin and Glucose and on Local Cerebral Glucose Utilization

Elevated blood levels of prolactin increase the synthesis, turnover, and release of 3,4-dihydroxyphenylethylamine (dopamine) from the tuberoinfundibular dopaminergic neurons, which project to the median eminence. The present study examined whether hyperprolactinemia also increases local cerebral glucose utilization, as determined by the 2-deoxy-D-[1-14C]glucose method, in the median eminence and other brain structures. Adult male rats were given ovine prolactin (4 mg/kg) subcutaneously every 8 h for 48 h. This treatment exerted an autoregulatory feedback effect on endogenous rat prolactin secretion, as evidenced by decreased circulating levels of rat prolactin. Ovine prolactin treatment also decreased plasma glucose concentrations. However, in both partially immobilized and free-ranging rats, glucose utilization in brain structures containing tuberoinfundibular dopaminergic cell bodies (the arcuate nucleus) and terminals (the median eminence) was not affected by ovine prolactin treatment. Hyperprolactinemia was, however, associated with decreased glucose utilization in the medial forebrain bundle and the CA subfield of the dorsal hippocampus. The lack of a significant effect of prolactin treatment on glucose utilization in the median eminence indicates that the resolution of the deoxyglucose technique, as used here, is not adequate to detect the ovine prolactin-induced increase in tuberoinfundibular dopaminergic neuronal activity, that the median eminence does not utilize glucose as its primary energy substrate, or that ovine prolactin treatment causes a counterbalancing decrease in the activity of other neurons projecting to the median eminence.     

Cerebral Metabolic Effects of Monoamine Oxidase Inhibition in Normal and 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Acutely Treated Monkeys

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces dopaminergic cell death in the substantia nigra pars compacta (SNpc) and clinical parkinsonism in humans and experimental animals. Pretreatment with monoamine oxidase inhibitors prevents this cell death and associated parkinsonism by blocking the oxidation of MPTP to a toxic intermediate. The 2-deoxyglucose method was used to study the acute effects of MPTP in the monkey brain and the effects of monoamine oxidase inhibition on local cerebral glucose utilization in both normal and MPTP-treated monkeys. MPTP administration alone caused a major increase in glucose utilization in the SNpc and smaller increases in some subnuclei within the ventral tegmental area in which eventual dopaminergic cell loss also occurs. Pretreatment with pargyline abolished these metabolic increases, a finding suggesting both that the oxidized product of MPTP generates the metabolic increases and that the increased glucose consumption may contribute to cell toxicity. On the other hand, in most cortical, thalamic, striatal, brainstem, and cerebellar areas MPTP alone caused reductions in glucose utilization, and pargyline failed to prevent these effects. Pargyline alone depressed metabolism in the locus coeruleus and a few other monoaminergic structures.     

Progesterone enhances ethanol-induced modulation of mesocortical dopamine neurons: antagonism by finasteride

The effect of endogenous 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐TH PROG) on the modulation of mesocortical dopamine extracellular concentration by ethanol was investigated by microdialysis in rats. Intraperitoneal injection of progesterone (5 mg/kg, once a day for 5 days) increased the cortical content of 3α,5α‐TH PROG and potentiated the biphasic effect of acute intraperitoneal administration of ethanol on dopamine content. A dose of ethanol (0.25 g/kg) that was ineffective in naïve rats induced a 55% increase in dopamine extracellular concentration in rats pretreated with progesterone. This increase was similar to that induced by a higher dose (0.5 g/kg) of ethanol in naïve rats. Administration of ethanol at 0.5 g/kg to progesterone‐pretreated rats inhibited dopamine content by an extent similar to that observed with an even higher dose (1 g/kg) in naïve rats. The administration of the 5α‐reductase inhibitor finasteride (25 mg/kg, subcutaneous), together with progesterone, prevented the effects of the latter, both on the cortical concentration of 3α,5α‐TH PROG and on the modulation by ethanol of dopamine content. These data suggest that 3α,5α‐TH PROG contributes to the action of ethanol on the mesocortical dopaminergic system. They also suggest that physiological fluctuations in the brain concentrations of neuroactive steroids associated with the oestrous cycle, menopause, pregnancy and stress may alter the response of mesocortical dopaminergic neurons to ethanol.     

Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.     

Comparative neurochemical changes associated with chronic administration of typical and atypical neuroleptics: implications in tardive dyskinesia

An important goal of current neuroleptic research is to develop antipsychotic compounds with the low incidence of extrapyramidal side effects. The therapeutic success and less side-effect of atypical anti-psychotics such as clozapine and risperidone has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated extrapyramidal side effects. The present study compares the effect of chronic administration of typical and atypical antipsychotics on neurochemical profile in rat forebrain. The study was planned to study changes in extracellular levels of norepinephrine, dopamine and serotonin in forebrain region of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements (VCM's), tongue protrusions and facial jerking) in rats, hall mark of chronic extrapyramidal side-effect of neuroleptic therapy tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in significant increase in orofacial hyperkinetic movements where as clozapine and risperidone showed less significant increase in orofacial hyperkinetic movements as compared to control. There were also significant decrease in the extracellular levels of neurotransmitters dopamine, norepinephrine and serotonin in fore-brain as measured by HPLC/ED after chronic administration of haloperidol and chlorpromazine. Chronic administration of atypical neuroleptics clozapine and risperidone resulted in the decrease in extracellular concentration of dopamine and norepinephrine but the effect was less significant as compared to typical drugs. However, treatment with atypical neuroleptics resulted in 3 fold increase in serotonin levels as compared to forebrain of control rats. Typical and atypical neuroleptics showed varying effects on neurotransmitters, especially serotonin which may account for the difference in their profile of side effects (Tardive dyskinesia).     

Vitamin B6 deficiency decreases the glucose utilization in cognitive brain structures of rats

The effects of vitamin B(6) deficiency on metabolic activities of brain structures were studied. Male Sprague-Dawley weanling rats received one of the following diets: (1) 7 mg pyridoxine HCl/kg (control group); (2) 0 mg pyridoxine HCl/kg (vitamin B(6)-deficient group); or (3) 7 mg pyridoxine HCl/kg with food intake restricted in quantity to that consumed by the deficient group (pair-fed control group). After 8 weeks of dietary treatment, rats in all three groups received an intravenous injection of 2-deoxy-[(14)C] glucose (100 microCi/kg). Vitamin B(6) status was evaluated by plasma pyridoxal 5'-phosphate concentrations. The vitamin B(6)-deficient group had significantly lower levels of plasma pyridoxal 5'-phosphate than did the control and pair-fed groups. The local cerebral glucose utilization rates in structures of the limbic system, basal ganglia, sensory motor system, and hypothalamic system were determined. The local cerebral glucose utilization rates in each of the four brain regions in the deficient animals were approximately 50% lower (P < 0.05) than in the control group. Results of the present study suggest that serious cognitive deficit may occur in vitamin B(6)-deficient animals.     

Differential effects of acute and chronic haloperidol treatment on striatal and nigral 3, 4-dihydroxyphenylacetic acid (DOPAC) levels

Chronic treatment of rats with haloperidol (4 weeks, 0.5 or 1 mg/kg) resulted in a significant attenuation of the large DOPAC rise seen in the corpus striatum after acute treatment. This tolerance effect was observed both shortly following termination of chronic treatment and on challenge with a low dose (0.1 mg/kg) of the drug 6–8 days later. In contrast, acute haloperidol treatment resulted in only a small and nonsignificant elevation of DOPAC levels in the substantia nigra, while chronic treatment caused a larger and significant increase in levels of the metabolite. Moreover, the latter effect was also observed in response to haloperidol challenge 6–8 days after discontinuation of drug treatment. The differential pattern of response in these two brain regions is discussed in relation to possible mechanisms mediating striatal tolerance and to recent observations regarding changes in nigral dopamine cell firing after chronic haloperidol treatment.     

DETERMINATION OF SOME MOLECULAR PARAMETERS OF TRYPTOPHAN HYDROXYLASE FROM RAT MIDBRAIN AND MURINE MAST CELL

Amphetamine, a potent sympathomimetic amine, has powerful stimulant actions in the central nervous system. These actions are believed to be related to the influence of amphetamine on release and uptake of catecholamine neurotransmitters. The [¹⁴C]deoxyglucose method makes it possible to study changes in cerebral metabolic rate in different areas of gray and white matter. Because of the close relationship between metabolic rate and functional activity, this method may be used to identify specific structures in the brain in which functional activity is altered. The [¹⁴C]deoxyglucose method was used to explore for changes in metabolic rate produced by d-and l-amphetamine (5 mg/kg) in forty gray and four white matter structures in normal conscious rats. d-Amphetamine produced increases in local cerebral glucose utilization in a number of components of the extrapyramidal motor system, as well as in some other structures known to contain dopamine-producing and/or dopaminoceptive cells. The largest increases after d-amphetamine administration occurred in the subthalamic nucleus and the zona reticulata of the substantia nigra. l-Amphetamine produced increases in some but not all of these same structures, and these were generally smaller than those observed with d-amphetamine. Decreases in local cerebral glucose utilization after either d- or l-amphetamine administration were found in the habenula and the suprachiasmatic nuclei of the hypothalamus. The effects in the suprachiasmatic nuclei may reflect their normal diurnal rhythm in metabolic rate. These results indicate that amphetamines may influence behavior through effects on specific regions of the brain. Only some of these regions have previously been studied as possible sites of action of amphetamine.     

Dopamine Release in Rat Striatum: Physiological Coupling to Tyrosine Supply

Intracerebral microdialysis was used to monitor dopamine release in rat striatal extracellular fluid following the intraperitoneal administration of dopamine's precursor amino acid, L-tyrosine. Dopamine concentrations in dialysates increased transiently after tyrosine (50-100 mg/kg) administration. Pretreatment with haloperidol or the partial lesioning of nigrostriatal neurons enhanced the effect of tyrosine on dopamine release, and haloperidol also prolonged this effect. These data suggest that nigrostriatal dopaminergic neurons are responsive to changes in precursor availability under basal conditions, but that receptor-mediated feedback mechanisms limit the magnitude and duration of this effect.     

Haloperidol does not alter a choice strategy for reinforcement value in cats

A blockade of the dopaminergic D1/D2 receptors by systemic administration of haloperidol (0.05-0.5 mg/kg) produced a dose-dependent increase in inhibition of conditioned alimentary behavior in cats under conditions of choice between a valuable delayed reward and a less valuable immediate reward. Administration of haloperidol produced a progressive decrease in the number of effective instrumental reactions, but did not affect the choice between short- and long-latency reactions and their mean latencies. The data obtained do not support a hypothesis that the blockade of dopaminergic receptors shifts behavior towards impulsive reactions. The reasons why the results do not support the hypothesis are discussed.     

Branched chain amino acid transaminases in brain in methionine sulphoximine (MSI) toxicity

The effect of intraperitoneal administration of L-methionine-DL-sulphoximine (MSI) was studied on branched-chain amino acid transaminases (BCAA-T) in different regions of rat brain and in liver. Administration of an acute dose of MSI (300 mg/kg body weight) resulted in a significant decrease in leucine aminotransferase activity in cerebral cortex, cerebellum, and brain-stem, while the activity of isoleucine aminotransferase was enhanced in hippocampus, corpus striatum, brain stem, and midbrain. Activities of both these enzymes changed marginally or remained unaltered in other regions of the brain. Valine aminotransferase showed a significant decrease in all the regions of the brain except in cerebellum. Following the administration of a sub-acute dose of MSI (150 mg/kg body wt.), the activities of the three BCAA aminotransferases were found to be enhanced in all regions of the brain. The results are discussed in relation to the utilization of BCAA for the production of glutamate and glutamine in hyperammonemia.     

Neuroprotective Effects of Alpha Lipoic Acid on Haloperidol-Induced Oxidative Stress in the Rat Brain

Haloperidol is an antipsychotic drug that exerts its' antipsychotic effects by inhibiting dopaminergic neurons. Although the exact pathophysiology of haloperidol extrapyramidal symptoms are not known, the role of reactive oxygen species in inducing oxidative stress has been proposed as one of the mechanisms of prolonged haloperidol-induced neurotoxicity. In the present study, we evaluate the protective effect of alpha lipoic acid against haloperidol-induced oxidative stress in the rat brain. Sprague Dawley rats were divided into control, alpha lipoic acid alone (100 mg/kg p.o for 21 days), haloperidol alone (2 mg/kg i.p for 21 days), and haloperidol with alpha lipoic acid groups (for 21 days). Haloperidol treatment significantly decreased levels of the brain antioxidant enzymes super oxide dismutase and glutathione peroxidase and concurrent treatment with alpha lipoic acid significantly reversed the oxidative effects of haloperidol. Histopathological changes revealed significant haloperidol-induced damage in the cerebral cortex, internal capsule, and substantia nigra. Alpha lipoic acid significantly reduced this damage and there were very little neuronal atrophy. Areas of angiogenesis were also seen in the alpha lipoic acid-treated group. In conclusion, the study proves that alpha lipoic acid treatment significantly reduces haloperidol-induced neuronal damage.     

Hypoglycemia activates compensatory mechanism of glucose metabolism of brain

The effect of plasma glucose concentration on the cerebral uptake of [18F]-fluorodeoxy-D-glucose (FDG) was studied in a broad concentration range in a rabbit brain model using dynamic FDG PET measurements. Hypoglycemic and hyperglycemic conditions were maintained by manipulating plasma glucose applying i.v. glucose or insulin load. FDG utilization (K) and cerebral glucose metabolic rate (CGMR) were evaluated in a plasma glucose concentration range between 0.5 mM and 26 mM from the kinetic constant k1, k2, k3 obtained by the Sokoloff model of FDG accumulation. A decreasing set of standard FDG uptake values found with increasing blood glucose concentration was explained by competition between the plasma glucose and the radiopharmacon FDG. A similar trend was observed for the forward kinetic constants k1, and k3 in the entire concentration range studied. The same decreasing tendency of k2 was of a smaller magnitude and was reverted at the lowest glucose concentrations where a pronounced decrease of this backward transport rate constant was detected. Our kinetic data indicate a modulation of the kinetics of carbohydrate metabolism by the blood glucose concentration and report on a special mechanism compensating for the low glucose supply under conditions of extremely low blood glucose level.     

Effect of beta-phenylethylamine on evoked potentials of the neostriatum of rats]

The effect of intraperitoneal (70 mg/kg) and local (39 ug) administration of beta-phenylethylamine (beta-PEA) on evoked potentials (EP) in the caudate nucleus upon stimulation of substantia nigra zona compacta (SNC) and frontal cortex in rats has been studied. beta-PEA, glutamate and haloperidol were injected into the caudate nucleus by means of a system consisting of a pushpull cannule and an electrode for simultaneous registration of EP. Specificity in the effect of the drugs on EP in response to stimulation of the cortex and substantia nigra was revealed. The intraperitoneal injection of beta-PEA induced, comparatively to the application, more rapid and potent decrease in the amplitude of the component (N2-P2) as a result of the substantia nigra stimulation and slightly influenced the EP amplitude in stimulation of the frontal cortex. It was established using haloperidol that the component (N2-P2) of EP in response to the substantia nigra stimulation is of dopaminergic neuron function in the nigro-neostrital system of the rat brain.     

Phencyclidine-induced stereotyped behavior and serotonergic syndrome in rat

Phencyclidine (50 mg/kg, i.p.) induced in rats a biphasic response consisting of serotonergic syndrome followed by stereotyped behavior. The initial serotonergic syndrome was significantly reduced by cinanserin (20 mg/kg, i.p.) and cyproheptadine (2.0 mg/kg, i.p.) but not influenced by haloperidol (0.5 mg/kg, i.p.). The later stereotyped behavior was significantly reduced by haloperidol (0.5 mg/kg, i.p.) but not influenced by cinanserin (20 mg/kg, i.p.) or cyproheptadine (2.0 mg/kg, i.p.). A lower dose of phencyclidine (5.0 mg/kg, i.p.) elicited only haloperidol-sensitive stereotyped behavior. These results indicate that serotonergic and dopaminergic mechanisms may mediate the behavioral effects of phencyclidine in rats.     

Functional Activity of Substantia Nigra Grafts Reinnervating the Striatum: Neurotransmitter Metabolism and [14C]2-Deoxy-d-glucose Autoradiography

Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudate-putamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudate-putamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplant-reinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral transplants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.     

Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats

Memory impairment induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats is associated with impaired brain glucose and energy metabolism, oxidative stress and impaired cholinergic neurotransmission. Treatment with antioxidants and cholinergic agonists has been reported to produce beneficial effect in this model. However, no reports are available on drugs that improve glucose utilization and metabolism. In the present study, we evaluated the effects of pioglitazone on cognitive performance, oxidative stress and glucose utilization in ICV STZ injected rats (3 mg/kg, on day 1 and 3). Pioglitazone (10 and 30 mg/kg) was administered per oral (p.o.) for 14 days, starting 5 days prior to STZ injection. Cognitive performance was assessed using step-through passive avoidance and Morris water maze task. Malondialdehyde (MDA) and glutathione levels in brain were estimated as parameters of oxidative stress. Glucose utilization by brain was assessed as the amount of glucose consumed from the media by the brain. ICV STZ injected rats showed a severe deficit in learning and memory associated with increased MDA levels (+67.5%), decreased glutathione levels (-29.2%) and impaired cerebral glucose utilization (-44.4%). In contrast pioglitazone treatment improved cognitive performance, lowered oxidative stress and improved cerebral glucose utilization in ICV STZ rats. The present study demonstrates the beneficial effects of pioglitazone in the ICV STZ induced cognitive deficits, which can be exploited for the dementia associated with diabetes and age-related neurodegenerative disorder, where oxidative stress and impaired glucose and energy metabolism are involved.