The age-old philosophical, biological, and social debate over the basic nature of humans as being "universally selfish" or "universally good" continues today highlighting sharply divergent views of ...natural social order. Here we analyze advances in biology, genetics and neuroscience increasing our understanding of the evolution, features and neurocircuitry of the human brain underlying behavior in the selfish-selfless spectrum. First, we examine evolutionary pressures for selection of altruistic traits in species with protracted periods of dependence on parents and communities for subsistence and acquisition of learned behaviors. Evidence supporting the concept that altruistic potential is a common feature in human populations is developed. To go into greater depth in assessing critical features of the social brain, the two extremes of selfish-selfless behavior, callous unemotional psychopaths and zealous altruists who take extreme measures to help others, are compared on behavioral traits, structural/functional neural features, and the relative contributions of genetic inheritance versus acquired cognitive learning to their mindsets. Evidence from population groups ranging from newborns, adopted children, incarcerated juveniles, twins and mindfulness meditators point to the important role of neuroplasticity and the dopaminergic reward systems in forming and reforming neural circuitry in response to personal experience and cultural influences in determining behavior in the selfish-selfless spectrum. The underlying neural circuitry differs between psychopaths and altruists with emotional processing being profoundly muted in psychopaths and significantly enhanced in altruists. But both groups are characterized by the reward system of the brain shaping behavior. Instead of rigid assignment of human nature as being "universally selfish" or "universally good," both characterizations are partial truths based on the segments of the selfish-selfless spectrum being examined. In addition, individuals and populations can shift in the behavioral spectrum in response to cognitive therapy and social and cultural experience, and approaches such as mindfulness training for introspection and reward-activating compassion are entering the mainstream of clinical care for managing pain, depression, and stress.
We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 ...months on a reduced-calorie diet 30% caloric restriction (CR) or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. ...Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.
In this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) into the striatum of rat was followed by immunocytochemical, histological, neurochemical and biochemical analyses. In addition, behavioral assessments including cylinder test and amphetamine-induced rotational behavior test were employed to validate ipsilateral damage to the dopamine nigrostriatal pathway. LPS injection caused progressive degeneration of the dopamine nigrostriatal system, which was accompanied by motor impairments including asymmetric usage of forelimbs and amphetamine-induced turning behavior in animals. Interestingly, some of the remaining nigral dopaminergic neurons had intracytoplasmic accumulation of alpha-synuclein and ubiquitin. Furthermore, defect in the mitochondrial respiratory chain, and extensive S-nitrosylation/nitration of mitochondrial complex I were detected prior to the dopaminergic neuronal loss. The mitochondrial injury was prevented by treatment with L-N(6)-(l-iminoethyl)-lysine, an iNOS inhibitor, suggesting that iNOS-derived NO is associated with the mitochondrial impairment.
These results implicate neuroinflammation-induced S-nitrosylation/nitration of mitochondrial complex I in mitochondrial malfunction and subsequent degeneration of the nigral dopamine neurons.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two ...trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. However, GDNF and neurturin Phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls. Insufficient drug distribution in the brain parenchyma has been proposed as a major contributing factor for the lack of clinical efficacy in the Phase-2 trial patients. To address this issue, a novel mammalian cell-derived variant form of GDNF (GDNFv) was designed to promote better tissue distribution by reducing its heparin binding to the extracellular matrix and key amino acids were substituted to enhance its chemical stability. Administration of this fully glycosylated GDNFv in the normal rat striatum increased dopamine turnover and produced significantly greater brain distribution than E. coli-produced wildtype GDNF (GDNFwt). Intrastriatal GDNFv also protected midbrain dopamine neuron function in 6-hydroxydopamine-lesioned rats. Studies conducted in normal adult rhesus macaques support that GDNFv was well tolerated in all animals and demonstrated a greater volume of distribution than GDNFwt in the brain following intrastriatal infusion. Importantly, favorable physiological activity of potential therapeutic value was maintained in this variant trophic factor with significant target activation in GDNFv recipients as indicated by dopamine turnover modulation. These data suggest that GDNFv may be a promising drug candidate for the treatment of PD. Additional studies are needed in non-human primates with dopamine depletion.
This article is part of the Special Issue entitled ‘Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders’.
•Neurotrophic factors have great therapeutic potential for Parkinson's disease.•Insufficient brain distribution has limited the clinical use of trophic factors.•A variant form of GDNF shows increased dopamine turnover and brain bioavailability.•GDNF variant is well tolerated in treated animals.•GDNF variant represents a promising drug candidate for treating parkinsonian patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To analyze a cluster of 30 industrial coworkers with Parkinson's disease and parkinsonism subjected to long‐term (8–33 years) chronic exposure to trichloroethylene.
Methods
Neurological ...evaluations were conducted on the 30 coworkers, including a general physical and neurological examination and the Unified Parkinson's Disease Rating Scale. In addition, fine motor speed was quantified and an occupational history survey was administered. Next, animal studies were conducted to determine whether trichloroethylene exposure is neurotoxic to the nigrostriatal dopamine system that degenerates in Parkinson's disease. The experiments specifically analyzed complex 1 mitochondrial neurotoxicity because this is a mechanism of action of other known environmental dopaminergic neurotoxins.
Results
The three workers with workstations adjacent to the trichloroethylene source and subjected to chronic inhalation and dermal exposure from handling trichloroethylene‐soaked metal parts had Parkinson's disease. Coworkers more distant from the trichloroethylene source, receiving chronic respiratory exposure, displayed many features of parkinsonism, including significant motor slowing. Neurotoxic actions of trichloroethylene were demonstrated in accompanying animal studies showing that oral administration of trichloroethylene for 6 weeks instigated selective complex 1 mitochondrial impairment in the midbrain with concomitant striatonigral fiber degeneration and loss of dopamine neurons.
Interpretation
Trichloroethylene, used extensively in industry and the military and a common environmental contaminant, joins other mitochondrial neurotoxins, MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) and some pesticides, as a risk factor for parkinsonism. Ann Neurol 2007
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman ...primate model of human aging. Six young (6–8 years old) and 6 aged (20–25 years old) female Rhesus monkeys ( Macaca mulatta ) were behaviorally characterized from standardized video records. Additionally, we measured mitochondrial bioenergetics along with calcium buffering capacity in the substantia nigra and putamen (PUT) from both age groups. Our results demonstrate that the aged animals had significantly reduced locomotor activity and movement speed compared with younger animals. Moreover, aged monkeys had significantly reduced ATP synthesis capacity (in substantia nigra and PUT), reduced pyruvate dehydrogenase activity (in PUT), and reduced calcium buffering capacity (in PUT) compared with younger animals. Furthermore, this age-related decline in mitochondrial function in the basal ganglia correlated with decline in motor function. Overall, our results suggest that drug therapies designed to enhance altered mitochondrial function may help improve motor deficits in the elderly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Glial cell line-derived neurotrophic factor (GDNF) has demonstrated significant antiparkinsonian actions in several animal models and in a recent pilot study in England in which four of five patients ...received bilateral putaminal delivery. In the present study the authors report on a 6-month unilateral intraputaminal GDNF infusion in 10 patients with advanced Parkinson disease (PD).
Patients with PD in a functionally defined on and off state were evaluated 1 week before and 1 and 4 weeks after intraputaminal catheter implantation in the side contralateral to the most affected side. Each patient was placed on a dose-escalation regimen of GDNF: 3, 10, and 30 microg/day at successive 8-week intervals, followed by a 1-month wash-out period. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores in the on and off states significantly improved 34 and 33%, respectively, at 24 weeks compared with baseline scores (95% confidence interval CI 18-47% for off scores and 16-51% for on scores). In addition, UPDRS motor scores in both the on and off states significantly improved by 30% at 24 weeks compared with baseline scores (95% CI 15-48% for off scores and 5-61% for on scores). Improvements occurred bilaterally, as measured by balance and gait and increased speed of hand movements. All significant improvements of motor function continued through the wash-out period. The only observed side effects were transient Lhermitte symptoms in two patients.
Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.
Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of ...Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I
125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I
125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm
3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2–9%) of the human putamen in the clinical trial using this catheter and infusion protocol.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Type 2 diabetes mellitus is the most common form of diabetes that occurs in both human and nonhuman primates. Although spontaneously diabetic nonhuman primates are used extensively in diabetic ...related research and are a proven valuable tool for the study of the natural history of diabetes, little is known about the key factors that can cause this metabolic disorder and the preventative measures that could be employed to minimize the consequences of diabetes. Using a model of developing and untreated diabetes, this study describes the effects of housing arrangement (socially group- versus individually single-housed), exercise, diet, age, and sex on fasting plasma glucose, key lipids associated with diabetes, and bodyweight in two large cohorts of nonhuman primates. Key findings include exercise/housing arrangement's contribution to significant differences in bodyweight, levels of fasting plasma glucose, total cholesterol, and high- and low-density lipoproteins. Age also had profound effects on glucose, triglyceride and high-density lipoproteins, particularly in single-caged animals. Moreover, females had higher fasting glucose, total cholesterol and triglyceride levels than male counterparts within the same housing situations. These factors may be critical to identifying preventive measures that could eventually be used to minimize obesity and diabetes in humans.
•Single housed non-human primates (NHP) have higher bodyweight than group housed.•Single-housed NHP have higher fasting glucose levels and lipid levels.•Limiting physical activity and social interaction promotes metabolic dysfunctions.•Gender differences in fasting glucose levels, total cholesterol and triglycerides.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Intracranial delivery to targeted brain areas tested in animals and clinical trials.•Implanted 120 intracranial catheters in 89 non-human primates.•MRI imaging was essential for assessing in situ ...patency.•Surgical strategies to maintain positive pressure increases likelihood of patency.
Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases.
We used a series of techniques, to in effect, maintain positive pressure inside the catheter relative to the outside, that included a hollow stylet, a high volume bolus of solution to clear the line, a low and slow continuous flow rate during implantation, and heat sealing the catheter at the time of implantation.
120 catheters implanted into brain parenchyma of 89 adult female rhesus monkeys across four sets of experiments. After experiencing a high delivery failure rate – non patent catheters – (19 %) because of tissue entrapment and debris and/or blood clots in the catheter tip, we developed modifications, including increasing the bolus infusion volume from 10 to 20 μl such that by the third experiment, the failure rate was 8 % (1 of 12 implants). Increasing the bolus volume to 100 μl and maintaining positive pressure in the catheter during preparation and implantation yielded a failure rate of 0 % (0/12 implants) by the fourth experiment.
We provide a retrospective analysis to reveal how several different manipulations affect catheter patency and how post-op MRI examination is essential for assessing catheter patency in situ.
The results of the present study identified that the main cause of the catheter blockages were clots that rendered the catheter non-patent. We resolved this by modifying the surgical procedures that prevented these clots from forming.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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