Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear

Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.

Cholinergic drugs bind at minor groove and reverse induced oxidative stress of calf thymus DNA: A new perspective towards an unexplored therapeutic efficacy

Conformational alterations in the structure of deoxyribonucleic acid (DNA) due to oxidative stress in the DNA backbone are known to be at the root of many life-threatening diseases. Clear comprehension...

The influence of cholinergic drugs on electroencephalogram of the gonadectomized female rabbits

The results of investigation has shown, that after the gonadectomy of the rabbits-females the general power of EEG spectrum (GPS of EEG) changed under influence of cholinergic drugs. The sterilizathion of the animals leads to disorders of interaction between M- and N-cholinergic mechanisms in the brain. In particular, blockade of M-cholinoreceptors by metamizyl in intact and ovariectomized rabbits increased the GPS of EEG. The simultaneous administration of metamizyl with galantamine to intact females led to even greater increase of GPS of EEG, whereas the sterilized rabbits demonstrated its reduction. On the contrary, the application of the N-cholinoreceptors inhibitor gangleron with inhibitor of acetylcholinesterase (AChE) galantamine reduced the GPS of EEG in intact animals and increased it in gonadectomized rabbits in comparison with gangleron alone. Thus, the effect of M,N-cholinoblockators in combination with AChE inhibitor in sterilized rabbits changed the EEG spectrum to opposite in comparison with intact females.

A fast genetically encoded fluorescent sensor for faithful in vivo acetylcholine detection in mice, fish, worms and flies

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.

Sebaceous and sweat gland disorders

Cutaneous glands in humans include holocrine or sebaceous glands and merocrine or sweat glands. Merocrine glands are subdivided into apocrine, eccrine, and apoeccrine glands. Disorders of each of these cutaneous glands have been associated with disease. Apocrine glands in adults are found predominantly in the axillae and anogenital regions, with a few located in the ear canal (ceruminous glands) and eyelids (Moll’s glands). Disorders associated with apocrine glands include hidradenitis suppurativa, Fox–Fordyce disease, bromhidrosis, trimethylaminuria, and chromhidrosis. Eccrine glands are the sweat-producing glands of the skin. Many drugs and systemic diseases can influence the degree of sweating, such as thyroid disease, infection, carcinoid, and cholinergic drugs. In cystic fibrosis, the concentration of sodium chloride in sweat is increased. Meanwhile, acne is a common inflammatory skin disease often associated with significant psychosocial morbidity.

The Pupil Diameter as a Possible Indicator of Neurodegenerative Diseases and Response to Acetylcholinesterase Inhibitors Therapy: In-Depth Measurements Following Topical Administration of Tropicamide and Pilocarpine

Background: The aim of this study is to assess whether pupillary modifications following ocular anticholinergic and cholinergic drugs can identify subjects with neurodegenerative diseases from early stages. Methods: 51 subjects were divided into 3 groups, according to different neurodegenerative diseases, and compared with a control group of 10 patients. Pupil diameter has been measured at different times after topical administration of tropicamide 0.01% in the right eye. Then, topical administration of pilocarpine 0.06% has been performed, followed by pupillary constriction measurement. Pupillary response rates were stratified according to acetylcholinesterase inhibitors intake. Results: Observed mydriasis and pupillary constriction was similar in all study groups at all evaluation times. Patients without acetylcholinesterase inhibitors intake presented greater mydriasis. Conclusions: Although it was not possible to observe significant differences among groups in terms of pupillary response, the analysis of pupillary features may become an useful tool to detect efficacy of acetylcholinesterase inhibitors.

The use of botulinum toxin for the treatment of patients with overactive bladder

Overactive bladder affects 12–17% of the population, and mainly women, and its incidence increases with age. Diagnosis of this condition is based mainly on the patients’ complaints. These symptoms significantly affect the quality of life of millions of patients, involving considerable social, psychological, professional, physical and sexual problems. The wide incidence of this condition makes it necessary to find new medical substances in order to effectively eliminate the symptoms. Neurotoxins are a group of medical drugs that hold great promise for the future. Botulinum toxin is currently being used to treat symptoms related to overactive bladder. It can constitute an appropriate therapeutic option, in particular with regard to patients for whom the use of standard anti-cholinergic drugs is unsatisfactory or leads to severe side effects. Numerous research studies confirm that botulinum toxin can be efficiently used in the treatment of overactive bladder. The properties of this neurotoxin allow selective deactivation of overactive muscles. The use of botulinum toxin can be a method of treatment that significantly improves patient quality of life.Keywords: botulinum toxin; overactive bladder; urinary incontinence; quality of life.