Pharmacologic fibroblast reprogramming into photoreceptors restores vision.

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision1,2. Chemical reprogramming of fibroblasts offers an opportunity to reverse vision loss; however, the generation of sensory neuronal subtypes such as photoreceptors remains a challenge. Here we report that the administration of a set of five small molecules can chemically induce the transformation of fibroblasts into rod photoreceptor-like cells. The transplantation of these chemically induced photoreceptor-like cells (CiPCs) into the subretinal space of rod degeneration mice (homozygous for rd1, also known as Pde6b) leads to partial restoration of the pupil reflex and visual function. We show that mitonuclear communication is a key determining factor for the reprogramming of fibroblasts into CiPCs. Specifically, treatment with these five compounds leads to the translocation of AXIN2 to the mitochondria, which results in the production of reactive oxygen species, the activation of NF-κB and the upregulation of Ascl1. We anticipate that CiPCs could have therapeutic potential for restoring vision.

Behavioral pharmacology of five novel synthetic cannabinoids.

Newly emerging synthetic cannabinoid compounds continue to be found in the designer drug market. They are often targeted as a 'legal high' alternative to traditional cannabinoids via 'darknet' markets and their increased potency and efficacy are becoming a growing concern internationally. The purpose of this study was to determine whether 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA exhibited similar behavioral effects as Δ9-tetrahydrocannabinol (Δ9-THC). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Male Sprague-Dawley rats were trained to discriminate between intraperitoneal injections of Δ9-THC (3 mg/kg) and vehicle. Following successful training, substitution tests for 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA were conducted. All of the test compounds decreased locomotor activity. 4-CN-CUMYL-BUTINACA (ED50 = 0.26 mg/kg), 4F-MDMB-BINACA (ED50 = 0.019 mg/kg), 5F-CUMYL-P7AICA (ED50 = 0.13 mg/kg) and EMB-FUBINACA (ED50 = 0.13 mg/kg) each fully substituted for the discriminative stimulus effects of the training dose of Δ9-THC, whereas 5F-AEB produced only a maximum of 67% drug-appropriate responding at 0.5 mg/kg. Higher doses produced piloerection, exophthalmos and convulsions. 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-CUMYL-P7AICA and EMB-FUBINACA are likely to produce similar subjective effects in humans as those produced by abused synthetic cannabinoids, and may therefore share similar abuse liability. In contrast, 5F-AEB may have a reduced abuse liability given its weaker THC-like discriminative stimulus effects but maybe more dangerous due to the adverse effects observed at doses needed to produce discriminative stimulus effects.

Behavioral effects of four novel synthetic cathinone analogs in rodents.

A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N-ethylhexedrone, 4-chloroethcathinone (4-CEC), and 4'-methyl-α-pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant-like effects to assess their abuse liability. Locomotor activity was assessed in an open-field assay using Swiss-Webster mice to screen for locomotor stimulant effects and to identify behaviorally-active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague-Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N-ethylhexedrone, 4-CEC, and MPHP dose-dependently increased locomotor activity. Dipentylone, N-ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4-CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4-CEC that produced peak effects lasted 2 to 3 h, the peak dose of N-ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4-CEC occurred at doses that substantially decreased response rate. Only 4-CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N-ethylhexedrone, 4-CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

Creatine, Creatine Kinase, and Aging.

With an ever aging population, identifying interventions that can alleviate age-related functional declines has become increasingly important. Dietary supplements have taken center stage based on various health claims and have become a multi-million dollar business. One such supplement is creatine, a major contributor to normal cellular physiology. Creatine, an energy source that can be endogenously synthesized or obtained through diet and supplement, is involved primarily in cellular metabolism via ATP replenishment. The goal of this chapter is to summarize how creatine and its associated enzyme, creatine kinase, act under normal physiological conditions, and how altered levels of either may lead to detrimental functional outcomes. Furthermore, we will focus on the effect of aging on the creatine system and how supplementation may affect the aging process and perhaps reverse it.

Transient focal cerebral ischemia induces long-term cognitive function deficit in an experimental ischemic stroke model.

Vascular dementia ranks as the second leading cause of dementia in the United States. However, its underlying pathophysiological mechanism is not fully understood and no effective treatment is available. The purpose of the current study was to evaluate long-term cognitive deficits induced by transient middle cerebral artery occlusion (tMCAO) in rats and to investigate the underlying mechanism. Sprague-Dawley rats were subjected to tMCAO or sham surgery. Behavior tests for locomotor activity and cognitive function were conducted at 7 or 30days after stroke. Hippocampal long term potentiation (LTP) and involvement of GABAergic neurotransmission were evaluated at 30days after sham surgery or stroke. Immunohistochemistry and Western blot analyses were conducted to determine the effect of tMCAO on cell signaling in the hippocampus. Transient MCAO induced a progressive deficiency in spatial performance. At 30days after stroke, no neuron loss or synaptic marker change in the hippocampus were observed. LTP in both hippocampi was reduced at 30days after stroke. This LTP impairment was prevented by blocking GABAA receptors. In addition, ERK activity was significantly reduced in both hippocampi. In summary, we identified a progressive decline in spatial learning and memory after ischemic stroke that correlates with suppression of hippocampal LTP, elevation of GABAergic neurotransmission, and inhibition of ERK activation. Our results indicate that the attenuation of GABAergic activity or enhancement of ERK/MAPK activation in the hippocampus might be potential therapeutic approaches to prevent or attenuate cognitive impairment after ischemic stroke.

Comparison of locomotor stimulant and drug discrimination effects of four synthetic cathinones to commonly abused psychostimulants.

BACKGROUND: The underground market is constantly flooded with newer synthetic as alternatives to the older cathinones. Drug Enforcement Administration (DEA) has identified four cathinone compounds of particular concern: 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (3,4-MD-α-PHP), 4-chloro-α-pyrrolidinopropiophenone (4-Cl-α-PPP), alpha-pyrrolidinoisohexiophenone (α-PiHP) and 4-chloro-pentedrone (4-Cl-pentedrone). AIMS: The current study aimed to evaluate the behavioral pharmacology of four synthetic cathinones. METHODS: 3,4-MD-α-PHP, 4-Cl-α-PPP, α-PiHP, and 4-CPD were tested for locomotor activity in mice and in a drug discrimination assay with rats trained to discriminate either methamphetamine or cocaine. RESULTS: Locomotor stimulant effects of 3,4-MD-α-PHP ((effective dose) ED50 = 1.98 mg/kg), α-PiHP (ED50 = 2.46 mg/kg), and 4-Cl-α-PPP (ED50 = 7.18 mg/kg) were observed within 10 min following injection and lasted from 2 to 3.5 h. The stimulant action of 4-CPD (ED50 = 17.24 mg/kg) was delayed, occurring 40-70 min following injection. The maximal motor stimulant actions of 3,4-MD-α-PHP and α-PiHP 1 were equivalent to that of cocaine and methamphetamine, whereas 4-CPD (50% of cocaine) and 4-Cl-α-PPP (73% of cocaine) were less efficacious. All of the test compounds fully substituted for the discriminative stimulus effects of cocaine, 3,4-MD-α-PHP (ED50 = 2.28 mg/kg), α-PiHP (ED50 = 3.84 mg/kg), and 4-Cl-α-PPP (ED50 = 15.56 mg/kg). Only 3,4-MD-α-PHP (ED50 = 1.65 mg/kg), α-PiHP (ED50 = 1.87 mg/kg), and 4-Cl-α-PPP (ED50 = 9.79 mg/kg) fully substituted for the discriminative stimulus effects of methamphetamine. 4-Cl-pentedrone caused 55-70% methamphetamine-appropriate responding at doses that also suppressed responding and produced convulsions. CONCLUSIONS: These data indicate that 3,4-MD-α-PHP, α-PiHP, and 4-Cl-α-PPP have a potential for abuse similar to that of methamphetamine and cocaine. In contrast, 4-Cl-pentedrone may not be popular for recreational use due to its convulsant effects.

Locomotor and discriminative stimulus effects of three benzofuran compounds in comparison to abused psychostimulants.

Aims: Benzofurans are used recreationally, due their ability to cause psychostimulant and/or entactogenic effects, but unfortunately produce substantial adverse effects, including death. Three benzofurans 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-MAPB) and 6-(2-aminopropyl) benzofuran (6-APB) were tested to determine their behavioral effects in comparison with 2,3-methylenedioxymethamphetamine (MDMA), cocaine, and methamphetamine. Methods: Locomotor activity was tested in groups of 8 male Swiss-Webster mice in an open-field task to screen for locomotor stimulant or depressant effects and to identify behaviorally active doses and times of peak effect. Discriminative stimulus effects were tested in groups of 6 male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg), cocaine (10 mg/kg), or methamphetamine (1 mg/kg) from saline using a FR 10 for food in a two-lever operant task. Results: In the locomotor activity test, MDMA (ED50 = 8.34 mg/kg) produced peak stimulant effects 60 to 80 min following injection. 5-MAPB (ED50 = 0.92 mg/kg) produced modest stimulant effects 50 to 80 min after injection, whereas 6-APB (ED50 = 1.96 mg/kg) produced a robust stimulant effect 20 to 50 min after injection. 5-APDB produced an early depressant phase (ED50 = 3.38 mg/kg) followed by a modest stimulant phase (ED50 = 2.57 mg/kg) 20 to 50 min after injection. In the drug discrimination tests, 5-APDB (ED50 = 1.02 mg/kg), 5-MAPB (ED50 = 1.00 mg/kg) and 6-APB (ED50 = 0.32 mg/kg) fully substituted in MDMA-trained rats, whereas only 5-MAPB fully substituted for cocaine, and no compounds fully substituted for methamphetamine. Conclusions: The synthetic benzofuran compound 5-APDB and 5-MAPB produced weak locomotor effects, whereas 6-APB produced robust locomotor stimulant effects. All compounds were more potent than MDMA. All three compounds fully substituted in MDMA-trained rats suggesting similar subjective effects. Taken together, these results suggest that these benzofuran compounds may have abuse liability as substitutes for MDMA.

Effects of chronic methamphetamine exposure on rewarding behavior and neurodegeneration markers in adult mice.

Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade and their use may increase vulnerability to brain biochemical changes and addictive behaviors. The long-term effects of chronic stimulant exposure in later adulthood have not been fully elucidated.Our study investigated whether chronic exposure to methamphetamine (METH), at a dose designed to emulate human therapeutic dosing for ADHD, would promote biochemical alterations and affect sensitivity to the rewarding effects of subsequent METH dosing.Groups of 3.5-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 1 month (5 days/week). METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the effects of previous METH exposure on reward-related behavior. Mice were randomly assigned to Experiment I (males and females) or Experiment II (females only) in which CPP testing was respectively performed either 0.5 or 5 months after the end of METH injections, at ~5 or 10 months old respectively. The midbrain and striatum, regions involved in reward circuit, were assessed for markers associated with neurotoxicity, dopaminergic function, neuroinflammation and epigenetic changes after behavioral testing.Previous exposure to chronic METH did not have significant short-term effects on CPP response but led to a decreased CPP response in 10-month-old females. Previous exposure to METH induced some short-term changes to biochemical markers measured in a brain region and sex-dependent manner, while long-term changes were only observed with GFAP and KDM5C.In conclusion, our data suggest sex- and post-exposure duration-dependent outcomes and warrant further exploration of the long-term neurobehavioral consequences of psychostimulant use in both sexes.

Expression of stable and reliable preference and aversion phenotypes following place conditioning with psychostimulants.

RATIONALE AND OBJECTIVES: Drug-seeking behavior occurs more readily in some individuals than others. This phenomenon is considered in studies of drug self-administration in which high drug-seeking/taking individuals can be identified. In contrast, studies of conditioned place preference (CPP) often involve a random sample of drug-naïve rodents that includes phenotypes not considered relevant to addiction. The main objective of the current studies was to determine if a priori identification of different conditioning phenotypes could improve the validity and sensitivity of CPP expression as a preclinical test for vulnerability to addiction. METHODS AND RESULTS: Analysis of cocaine place conditioning data from 443 Swiss-Webster mice revealed a trimodal distribution with peaks corresponding to means of k = 3 clusters. The cluster means occurred at high, low, or negative preference scores, the latter suggesting a phenotype acquiring conditioned place aversion (CPA). The same clusters were identified in mice conditioned with methamphetamine, MDPV, or amphetamine, and these clusters remained stable and reliable during three additional expression tests spaced at 24 h. A meta-analysis of effect sizes obtained from CPP literature revealed a positively skewed distribution affected by sample size, consistent with the existence of a CPA phenotype within the populations tested. A dopamine receptor antagonist, flupentixol, blocked cocaine CPP expression in a group containing all phenotypes, but sensitivity improved markedly when CPA phenotypes were excluded from the dataset. CONCLUSIONS: These studies suggest that taking phenotype into consideration when designing place conditioning studies will improve their application as a preclinical tool in addiction biology and drug discovery.

Sex differences in neurobehavioral consequences of methamphetamine exposure in adult mice.

RATIONALE: Recreational and medical use of stimulants is increasing, and their use may increase susceptibility to aging and promote neurobehavioral impairments. The long-term consequences of these psychostimulants and how they interact with age have not been fully studied. OBJECTIVES: Our study investigated whether chronic exposure to the prototypical psychostimulant, methamphetamine (METH), at doses designed to emulate human therapeutic dosing, would confer a pro-oxidizing redox shift promoting long-lasting neurobehavioral impairments. METHODS: Groups of 4-month-old male and female C57BL/6 J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 4 weeks. Mice were randomly assigned to one experimental group: (i) short-term cognitive assessments (at 5 months), (ii) long-term cognitive assessments (at 9.5 months), and (ii) longitudinal motor assessments (at 5, 7, and 9 months). Brain regions were assessed for oxidative stress and markers of neurotoxicity after behavior testing. RESULTS: Chronic METH exposure induced short-term effects on associative memory, gait speed, dopamine (DA) signaling, astrogliosis in females, and spatial learning and memory, balance, DA signaling, and excitotoxicity in males. There were no long-term effects of chronic METH on cognition; however, it decreased markers of excitotoxicity in the striatum and exacerbated age-associated motor impairments in males. CONCLUSION: In conclusion, cognitive and motor functions were differentially and sex-dependently affected by METH exposure, and oxidative stress did not seem to play a role in the observed behavioral outcomes. Future studies are necessary to continue exploring the long-term neurobehavioral consequences of drug use in both sexes and the relationship between aging and drugs.

Prolonged intake of coenzyme Q10 impairs cognitive functions in mice.

Coenzyme Q(10) (CoQ(10)) is widely consumed as a dietary supplement to enhance bioenergetic capacity and to ameliorate the debilitative effects of the aging process or certain pathological conditions. Our main purpose in this study was to determine whether CoQ(10) intake does indeed attenuate the age-associated losses in motor, sensory, and cognitive functions or decrease the rate of mortality in mice. Mice were fed a control nonpurified diet or that diet containing 0.68 mg/g (low dosage) or 2.6 mg/g (high dosage) CoQ(10), starting at 4 mo of age, and were tested for sensory, motor, and cognitive function at 7, 15, and 25 mo of age. Amounts of the ubiquinols CoQ(9)H(2) and CoQ(10)H(2) measured in a parallel study were augmented in the cerebral cortex but not in any other region of the brain. Intake of the low-CoQ(10) diet did not affect age-associated decrements in muscle strength, balance, coordinated running, or learning/memory, whereas intake at the higher amount increased spontaneous activity, worsened the age-related losses in acuity to auditory and shock stimuli, and impaired the spatial learning/memory of old mice. The CoQ(10) diets did not affect survivorship of mice through 25 mo of age. Our results suggest that prolonged intake of CoQ(10) in low amounts has no discernable impact on cognitive and motor functions whereas intake at higher amounts exacerbates cognitive and sensory impairments encountered in old mice. These findings do not support the notion that CoQ(10) is a fitness-enhancing or an "antiaging" substance under normal physiological conditions.

Impure but not inactive: Behavioral pharmacology of dibenzylpiperazine, a common by-product of benzylpiperazine synthesis.

BACKGROUND: Substituted piperazines comprise a substantial proportion of the novel psychoactive substance market. Among the most widely abused piperazine compounds are meta-chlorophenylpiperazine (mCPP), tri-fluoromethylphenylpiperazine (TFMPP), and, especially, benzylpiperazine (BZP), which are commonly incorporated, either alone or in combination, in illicit "party pills" or "ecstasy" formulations. Illicit synthesis of BZP often results in production of an impure by-product dibenzylpiperazine (DBZP), which frequently appears alongside BZP in these formulations; however, despite its ubiquity, little information exists regarding the abuse liability of DBZP. AIMS: The current study aimed to evaluate the abuse-related behavioral pharmacology of DBZP. METHODS: DBZP, mCPP, and TFMPP were tested in parallel in mice in locomotor activity and conditioned place preference assays, and in a drug discrimination assay with rats trained to discriminate either methamphetamine, cocaine, (±)-3,4-methylenedioxymethamphetamine (MDMA), or -2,5-dimethoxy-4-methylamphetamine(DOM). RESULTS: Each of the compounds tested produced dose-dependent decreases in locomotor activity. DBZP substituted fully for methamphetamine, produced subthreshold drug-appropriate responding for cocaine and MDMA, and failed to substitute for DOM. Conversely, TFMPP and mCPP only produced subthreshold drug-appropriate responding for methamphetamine and MDMA, respectively, and both compounds failed to substitute for cocaine or DOM. None of the compounds tested produced a place preference. DBZP produced convulsions in rats at the highest dose tested. CONCLUSIONS: These data indicate that DBZP is more similar to BZP, albeit with lower potency and efficacy, than its serotonergic piperazine counterparts, and is a behaviorally-active compound with some abuse liability and potential for adverse health effects.

Retrograde conditioning of place preference and motor activity with cocaine in mice.

RATIONALE: In order to improve understanding of the nature of drug-associated memory, the current studies addressed whether conditioned place preference (CPP) could develop under conditions in which there was a delay between presentation of context and drug exposure (i.e., retrograde or trace conditioning). OBJECTIVES: The objective was to assess development of CPP when cocaine or methamphetamine was injected simultaneously with exposure to a salient context (S+), or after delays differing in length. METHODS: Dose response curves for conventional CPP were established using separate groups of Swiss-Webster mice injected with cocaine or methamphetamine just prior to S+ exposure. To assess the development of retrograde CPP, other groups received trace conditioning, where cocaine (15 mg/kg) or methamphetamine (0.5 mg/kg) was injected after a delay of 15, 60, 120, 180, 240, or 480 min following the end of the S+ session. RESULTS: Mice receiving conventional CPP with cocaine or methamphetamine during S+ showed significant place preference. None of the groups receiving delayed methamphetamine showed significant CPP; however, CPP was evident in mice receiving cocaine after delays of up to 4 h following S+. In a separate study, delayed methamphetamine also did not result in significant place preference when presented in doses of 0.25 or 1 mg/kg. CONCLUSIONS: These results suggest that psychostimulant drug taking may be broadly generalized to context through retrograde association with events in recent memory, a factor that may contribute to drug-seeking and relapse following abstinence.

Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia.

Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer's disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.

Coenzyme Q10 and α-tocopherol reversed age-associated functional impairments in mice.

The purpose of this study was to determine if intake of the antioxidants coenzyme Q10 (CoQ10) or α-tocopherol (Toc), either alone or in combination, could ameliorate cognitive and psychomotor impairments of aged mice, as well as reduce oxidative burden in tissues. For a period of 10 weeks, male C57BL/6J mice (3 or 18 months) were fed either a control diet, or one of three diets supplemented with Toc, CoQ10 or their combination, and were tested for cognitive and psychomotor functions. Old mice on the Toc or Toc/CoQ10 diets showed improved coordinated running performance. Mice on the diet containing Toc/CoQ10 demonstrated improved performance in the discriminated avoidance task. CoQ10 and Toc alone also resulted in improved performance, albeit to a lesser degree. Protein damage was decreased especially when the mice received Toc+CoQ10 combination. Overall, these results suggest that, Toc and CoQ supplementation can ameliorate age-related impairment and reduce protein oxidation. Moreover, concurrent supplementation of CoQ10 and Toc may be more effective than either antioxidant alone.

Coenzyme Q(10) supplementation reverses age-related impairments in spatial learning and lowers protein oxidation.

Coenzyme Q10 (CoQ) is widely available as a dietary supplement and remains under consideration as a treatment for age-associated neurodegenerative conditions. However, no studies have determined if supplementation, initiated relatively late in life, could have beneficial effects on mild functional impairments associated with normal brain aging. Accordingly, the current study assessed the effect of CoQ intake in older mice for which cognitive and psychomotor impairments were already evident. Separate groups of young (3.5 months) and relatively old mice (17.5 months) were fed a control diet or a diet supplemented with low (0.72 mg/g) or high (2.81 mg/g) concentrations of CoQ for 15 weeks. After 6 weeks, the mice were given tests for spatial learning (Morris water maze), spontaneous locomotor activity, motor coordination, and startle reflex. Age-related impairments in cognitive and psychomotor functions were evident in the 17.5-month-old mice fed the control diet, and the low-CoQ diet failed to affect any aspect of the impaired performance. However, in the Morris water maze test, old mice on the high-CoQ diet swam to the safe platform with greater efficiency than the mice on the control diet. The old mice supplemented with the high-CoQ diet did not show improvement when spatial performance was measured using probe trials and failed to show improvement in other tests of behavioral performance. Protein oxidative damage was decreased in the mitochondria from the heart, liver, and skeletal muscle of the high-CoQ-supplemented mice and, to some extent, in the brain mitochondria. Contrasting with the deleterious effect of long-term CoQ supplementation initiated during young adulthood previously published, this study suggests that CoQ improves spatial learning and attenuates oxidative damage when administered in relatively high doses and delayed until early senescence, after age-related declines have occurred. Thus, in individuals with age-associated symptoms of cognitive decline, high-CoQ intake may be beneficial.