Vigorous Aerobic Exercise in the Management of Parkinson Disease: A Systematic Review.

OBJECTIVE: To summarize the findings from studies examining the effects of vigorous-intensity aerobic exercise in the management of Parkinson disease. TYPE: Systematic review. LITERATURE SURVEY: PubMed/MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Library, SPORTDiscus, and ScienceDirect databases were searched up to May 2020. Reference lists of the included articles were also searched for additional studies. Searches were restricted to English language. METHODOLOGY: Seven papers, including six studies, five randomized controlled trials and one controlled trial, were identified. The studies examined the effects of vigorous-intensity aerobic exercise in participants with Parkinson disease. Studies in which the minimal intensity required was ≥77% of maximum heart rate, 60% of heart rate reserve or 64% of maximal oxygen uptake met the inclusion criteria. Method appraisal showed a mean score of 5.3 in the Physiotherapy Evidence Database (PEDro) scale. SYNTHESIS: No statistically significant differences were found between vigorous-intensity aerobic exercise and moderate/low-intensity aerobic exercise for the main outcomes (disease severity and motor function). Only one study concluded a significant higher aerobic fitness in favor of the group that exercised at vigorous intensity compared to the moderate intensity group. CONCLUSIONS: Vigorous-intensity aerobic exercise has not shown statistically significant improvements in motor and nonmotor impairments in individuals with Parkinson disease as compared to moderate/low-intensity aerobic exercise. Hence, the current evidence is too limited to allow recommendations for clinical practice.

Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice.

Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8BAC -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8+ corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8+ corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.

TRPM8.

Transient receptor potential melastatin 8 (TRPM8) was originally cloned from prostate tissue. Shortly thereafter, the protein was identified as a cold- and menthol-activated ion channel in peripheral sensory neurons, where it plays a critical role in cold temperature detection. In this chapter, we review our current understanding of the molecular and biophysical properties, the pharmacology, and the modulation by signaling molecules of this TRP channel. Finally, we examine the physiological role of TRPM8 and its emerging link to various human diseases, including pain, prostate cancer, dry eye disease, and metabolic disorders.

Cyclic AMP and Epac contribute to the genesis of the positive interaction between hypoxia and hypercapnia in the carotid body.

Carotid body chemoreceptor cells in response to hypoxic and hypercapnic stimulus increase their resting rate of release of neurotransmitters and their action potential frequency in the carotid sinus sensory nerve. When chemoreceptor activity is assessed at the level of the carotid sinus nerve and on ventilation, there exists an interaction between hypoxic and hypercapnic stimulus so that the response to both stimuli combined is additive or more than additive, over a wide range of stimulation. It is not clear if this interaction occurs at chemoreceptor cell or directly acting on the sensory nerve. In the present work we demonstrate for the first time the existence of a positive interaction between hypoxic and hypercapnic-acidotic stimuli at the level of both, membrane potential depolarization and neurotransmitter release in rat and rabbit carotid body. Inhibition of adenylate cyclase (SQ-22536) abolished the positive interaction between stimuli and the Epac (exchange proteins activated by cAMP) activator 8-pCPT-2'-O-Me-cAMP reversed the effect of adenylate cyclase inhibition. These results suggest that this interaction between the two natural stimuli is mediated by cAMP via an Epac-dependent pathway, at least at the level of neurotransmitter release.

EPAC signalling pathways are involved in low PO2 chemoreception in carotid body chemoreceptor cells.

Chemoreceptor cells of the carotid bodies (CB) are activated by hypoxia and acidosis, responding with an increase in their rate of neurotransmitter release, which in turn increases the electrical activity in the carotid sinus nerve and evokes a homeostatic hyperventilation. Studies in isolated chemoreceptor cells have shown that moderate hypoxias ( 46 mmHg) produces smaller depolarisations and comparable Ca(2+) transients but a much higher catecholamine (CA) release response in intact CBs than intense acidic/hypercapnic stimuli (20% CO(2), pH 6.6). Similarly, intense hypoxia ( 20 mmHg) produces smaller depolarizations and Ca(2+) transients in isolated chemoreceptor cells but a higher CA release response in intact CBs than a pure depolarizing stimulus (30-35 mm external K(+)). Studying the mechanisms responsible for these differences we have found the following. (1) Acidic hypercapnia inhibited I(Ca) (60%; whole cell) and CA release (45%; intact CB) elicited by ionomycin and high K(+). (2) Adenylate cyclase inhibition (SQ-22536; 80 microm) inhibited the hypoxic release response (>50%) and did not affect acidic/hypercapnic release, evidencing that the high gain of hypoxia to elicit neurotransmitter release is cAMP dependent. (3) The last effect was independent of PKA activation, as three kinase inhibitors (H-89, KT 5720 and Rp-cAMP; 10 x IC(50)) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8-pCPT-2-O-Me-cAMP, 100 microm) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 microm) inhibited (54%) hypoxic induced release. Our findings show for the first time that an Epac-mediated pathway mediates O(2) sensing/transduction in chemoreceptor cells.

Role of voltage-dependent calcium channels in stimulus-secretion coupling in rabbit carotid body chemoreceptor cells.

We have defined Ca2+ channel subtypes expressed in rabbit carotid body (CB) chemoreceptor cells and their participation in the stimulus-evoked catecholamine (CA) release. Ca2+ currents (I(Ca)) activated at -30 mV, peaked at +10 mV and were fully blocked by 200 microm Cd2+. L-type channels (sensitive to 2 microm nisoldipine) activated at -30 mV and carried 21 +/- 2% of total I(Ca). Non-L-type channels activated at potentials positive to -10 mV and carried: N channels (sensitive to 1 microM omega-conotoxin-GVIA) 16 +/- 1% of total I(Ca), P/Q channels (sensitive to 3 microM omega-conotoxin-MVIIC after nisoldipine plus GVIA) 23 +/- 3% of total I(Ca) and R channels (resistant to all blockers combined) 40 +/- 3% of total I(Ca). CA release induced by hypoxia, hypercapnic acidosis, dinitrophenol (DNP) and high K(+)(o) in the intact CB was inhibited by 79-98% by 200 microm Cd2+. Hypoxia, hypercapnic acidosis and DNP, depolarized chemoreceptor cells and eventually generated repetitive action potential discharge. Nisoldipine plus MVIIC nearly abolished the release of CAs induced by hypoxia and hypercapnic acidosis and reduced by 74% that induced by DNP. All these secretory responses were insensitive to GVIA. 30 and 100 mm K(+)(o) brought resting membrane potential (E(m)) of chemoreceptor cells (-48.1 +/- 1.2 mV) to -22.5 and +7.2 mV, respectively. Thirty millimolar K(+)(o)-evoked release was abolished by nisoldipine but that induced by 100 mm K(+)(o) was mediated by activation of L, N, and P/Q channels. Data show that tested stimuli depolarize rabbit CB chemoreceptor cells and elicit CA release through Ca2+ entry via voltage-activated channels. Only L and P/Q channels are tightly coupled to the secretion of CA.