Oral curcumin supplementation improves fine motor function in the middle-aged rhesus monkey.

Aged individuals experience decreased fine motor function of the hand and digits, which could result, in part, from the chronic, systemic state of inflammation that occurs with aging. Recent research for treating age-related inflammation has focused on the effects of nutraceuticals that have anti-inflammatory properties. One particular dietary polyphenol, curcumin, the principal curcuminoid of the spice turmeric, has been shown to have significant anti-inflammatory effects and there is mounting evidence that curcumin may serve to reduce systemic inflammation. Therefore, it could be useful for alleviating age-related impairments in fine motor function. To test this hypothesis we assessed the efficacy of a dietary intervention with a commercially available optimized curcumin to ameliorate or delay the effects of aging on fine motor function of the hand of rhesus monkeys. We administered oral daily doses of curcumin or a control vehicle to 11 monkeys over a 14- to 18-month period in which they completed two rounds of fine motor function testing. The monkeys receiving curcumin were significantly faster at retrieving a food reward by round 2 of testing than monkeys receiving a control vehicle. Further, the monkeys receiving curcumin demonstrated a greater degree of improvement in performance on our fine motor task by round 2 of testing than monkeys receiving a control vehicle. These findings reveal that fine motor function of the hand and digits is improved in middle-aged monkeys receiving chronic daily administration of curcumin.

Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy.

Cortical neuron death is prevalent by 9 months in rTg(tau(P301L))4510 tau mutant mice (TG) and surviving pyramidal cells exhibit dendritic regression and spine loss. We used whole-cell patch-clamp recordings to investigate the impact of these marked structural changes on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) of layer 3 pyramidal cells in frontal cortical slices from behaviorally characterized TG and non-transgenic (NT) mice at this age. Frontal lobe function of TG mice was intact following a short delay interval but impaired following a long delay interval in an object recognition test, and cortical atrophy and cell loss were pronounced. Surviving TG cells had significantly reduced dendritic diameters, total spine density, and mushroom spines, yet sEPSCs were increased and sIPSCs were unchanged in frequency. Thus, despite significant regressive structural changes, synaptic responses were not reduced in TG cells, indicating that homeostatic compensatory mechanisms occur during progressive tauopathy. Consistent with this idea, surviving TG cells were more intrinsically excitable than NT cells, and exhibited sprouting of filopodia and axonal boutons. Moreover, the neuropil in TG mice showed an increased density of asymmetric synapses, although their mean size was reduced. Taken together, these data indicate that during progressive tauopathy, cortical pyramidal cells compensate for loss of afferent input by increased excitability and establishment of new synapses. These compensatory homeostatic mechanisms may play an important role in slowing the progression of neuronal network dysfunction during neurodegenerative tauopathies.

Chronic curcumin treatment improves spatial working memory but not recognition memory in middle-aged rhesus monkeys.

Studies of both humans and non-human primates have demonstrated that aging is typically characterized by a decline in cognition that can occur as early as the fifth decade of life. Age-related changes in working memory are particularly evident and mediated, in part, by the prefrontal cortex, an area known to evidence age-related changes in myelin that is attributed to inflammation. In recent years, several nutraceuticals, including curcumin, by virtue of their anti-inflammatory and antioxidant effects, have received considerable attention as potential treatments for age-related cognitive decline and inflammation. Accordingly, we assessed for the first time in a non-human primate model of normal aging the efficacy of dietary intervention using the natural phenol curcumin to ameliorate the effects of aging on spatial working and recognition memory. Results revealed that monkeys receiving daily administration of curcumin over 14-18 months demonstrated a greater improvement in performance on repeated administration of a task of spatial working memory compared to monkeys that received a control substance.

Prenatal protein malnutrition enhances stimulus control by CDP, but not a CDP/THIP combination in rats.

In the present study, the effects of prenatal protein malnutrition on stimulus control exerted by the benzodiazepine (BZ), chlordiazepoxide (CDP) and the GABA-A receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) were characterized. The adult, male offspring of female Sprague-Dawley rats fed either low (6% casein) or adequate (25% casein) protein diets 5 weeks prior to mating and throughout pregnancy served as subjects. Subjects were first trained to discriminate CDP (8.0 mg/kg ip) from saline using drug discrimination procedures. Once a criterion level of performance was achieved, generalization tests were performed to lower doses of CDP (4.0, 2.0, 1.0, 0.5 and 0.25 mg/kg) and then to several doses of THIP (10.0, 7.5, 5.6 and 3.2 mg/kg). Lastly, the ability of a single dose of THIP (3.0 mg/kg) to enhance discriminative control by several low doses of CDP (4.0, 2.0, 1.0 and 0.5 mg/kg) was assessed. Although both diet groups acquired the original CDP/saline discrimination at the same rate, malnourished rats exhibited significantly more generalization to low doses of CDP than their well-nourished counterparts. Neither diet group exhibited significant generalization to THIP nor a difference in THIP's ability to enhance the CDP cue. These results suggest that a subject's sensitivity to the stimulus properties of drugs can be selectively modified by prenatal malnutrition.

Ultrasonic call characteristics of rat pups are altered following prenatal malnutrition.

The male offspring of rats provided with a protein deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy were subjected to a brief period of isolation and cooling at postnatal Days (P)7, 9, and 11, and their ultrasonic vocalizations were compared with those of well-nourished pups. Calls were categorized into 12 different types based upon their sonographic patterns. Although call rates were equal, the call characteristics of the prenatally malnourished pups differed significantly from those of well-nourished controls. At P7, their mean peak sound frequency (irrespective of call type) was significantly higher, and constant frequency calls were of both higher frequency and longer duration. Over the age range studied, prenatally malnourished pups emitted a smaller variety of calls, with significantly fewer ascending frequency vocalizations while producing either significantly fewer (P9) or greater (P11) descending frequency calls. Altered crying patterns have been related to brain damage in human babies, with more abnormal cries being associated with more severe neurological impairment. Therefore, the present results most likely reflect altered central nervous system development and function. Ultrasonic vocalization characteristics in rat pups may provide a useful early marker of the severity of disturbance to the development of the central nervous system following an insult, and offer the potential for predicting the degree of functional and behavioral deficits later in life.