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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 16  |  Issue : 2  |  Page : 111-115

Dose-dependent quinine toxicity of intracranial auditory relay centre (inferior colliculus) in male albino Wistar rats is reversible


1 Department of Anatomy, Faculty of Basic Medical Sciences, University of Uyo, Uyo, Nigeria
2 Department of Anatomy, Faculty of Basic Medical Science, University of Calabar, Calabar, Nigeria

Date of Web Publication4-Jun-2018

Correspondence Address:
Dr. Idorenyin U Umoh
Department of Anatomy, Faculty of Basic Medical Sciences, University of Uyo, Uyo
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jeca.jeca_7_17

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  Abstract 


BACKGROUND: The toxicity of quinine treatment on intracranial auditory relay center, inferior colliculus (IC), of male albino Wistar rats was investigated.
MATERIALS AND METHOD: Thirty-five male rats weighing between 180 and 200 g were used for the study. They were randomly divided into seven groups of five animals per group with Group 1 serving as the control. Groups 2, 3, and 4 received 10, 20, and 30 mg of quinine per kilogram body weight, respectively, for 7 days, while Groups 5, 6, and 7 received 10, 20, and 30 mg of quinine per kilogram body weight, respectively, for 7 days and then allowed to recover over time for another 7 days. The animals were sacrificed under chloroform anesthesia; The brain tissues were perfused with phosphate buffer solution, harvested, processed, stained using hematoxylin and eosin staining technique and observed histologically under light microscope.
RESULTS: The IC of the Group 1 (control) showed normal histological features with the neurons appearing distinct with conspicuous cellular population. Seven-day quinine-treated groups (Groups 2–4) revealed mild-to-severe cellular distortion. Seven days after the withdrawal of quinine, the tissue sections appeared to have recovered completely with more neuronal density and cellular regeneration in the IC of Groups 5, 6, and 7. This study has revealed that quinine induces a dose-dependent toxicity on the IC of rats.
CONCLUSION: It can also be concluded that, there is likelihood of complete natural recovery of the cellular cytoarchitecture and neuronal cell regeneration after 7 days of withdrawal of quinine.

Keywords: Histomorphology, inferior colliculus, neurotoxicity, quinine


How to cite this article:
Umoh IU, Ekanem TB. Dose-dependent quinine toxicity of intracranial auditory relay centre (inferior colliculus) in male albino Wistar rats is reversible. J Exp Clin Anat 2017;16:111-5

How to cite this URL:
Umoh IU, Ekanem TB. Dose-dependent quinine toxicity of intracranial auditory relay centre (inferior colliculus) in male albino Wistar rats is reversible. J Exp Clin Anat [serial online] 2017 [cited 2018 Sep 26];16:111-5. Available from: http://www.jecajournal.org/text.asp?2017/16/2/111/233681




  Introduction Top


Quinine is indicated medically as antimalarial, nonnarcotic, analgesic, anti-inflammatory, muscle relaxants centrally acting to treat nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels (Taylor 1996). It is also used as antiprotozoal, antispasmodic, appetite stimulant and for the treatment of arrhythmias (Taylor 1996). Quinine is also used to flavor carbonated drinks or tonic water because of its bitter taste. It has been reported that 100 mg of quinine taken in tonic water is sufficient to produce positional abnormalities in electronystagmography. The drug was also used as an adulterant in heroine because it is a bitter taste, disguised dilution (Heybach and Boyle 1982). Furthermore, due to its oxytocic activity, quinine was used intravenously to induce abortion (Ballestero et al. 2005). Since its oxytocic activity is ineffective when taken orally, repeated oral doses may give rise to overdose (Ballestero et al. 2005).

Quinine is administered at a dosage of 20 mg/kg body weight intravenously followed by 10 mg/kg body weight every 8 h (World Health Organization 2010). However, the high loading dose can result in several adverse effects and toxicity and even the risk of death (Lesi and Meremikwu 2004). Quinine is distributed throughout the body fluid, and it is highly bound to protein mainly alpha-1 acid glycoprotein and also crosses the placental barrier. Hepatic biotransformation excretes about 80% of the administered dose while the other 20% is eliminated unchanged by the kidney (White 1996).

Several adverse effects have been reported to be associated with the use of quinine, coupled with its low therapeutic index (World Health Organization 2010). The side effects commonly observed at therapeutic concentration of quinine are referred to as cinchonism, with mild forms including tinnitus, slight-hearing impairment, headache, and nausea (World Health Organization 2000). Impairment of hearing is usually concentration dependent and reversible (Karlsson 1990). More severe manifestation includes vertigo, vomiting, abdominal pain, diarrhea, marked auditory loss, and visual symptoms. Neurotoxic features may include ataxia, vertigo, syncope, confusion, and delirium (Wolf et al. 1992; Goldenberg and Wexler 1988).

The inferior colliculus (IC) is an important auditory relay center for ascending pathways, and the central nucleus of IC receives input from lower auditory centers and projects to the medial geniculate body (MGB) in a strictly tonotopic manner. Most ascending auditory tracts converge on the IC, which is a major relay en route to the MGB (Malmierca et al. 2003). Afferent projections to the IC are both excitatory and inhibitory (Shneiderman and Henkel 1987; Saint Marie et al. 1989). Likewise, projections from the IC to the MGB are also excitatory and inhibitory (Barlett et al. 2000). The IC is the major processing center in the auditory midbrain (Irvine 1992). Toxicity of xenobiotic to the IC can be deleterious to hearing. This study was designed to investigate the toxicity of quinine treatment on one of the auditory relay centers (IC) and the reversibility of the toxicity after stoppage of administration of quinine to albino rats.


  Materials and Methods Top


Injectable quinine was obtained from Buchler GmbH, Germany. Thirty-five male albino Wistar rats weighing 180–200 g were used for the study. They were obtained from the Animal House of College of Health Sciences, University of Uyo, Nigeria. They were acclimatized for 2 weeks during which they were fed with rat chow and water ad libitum. The animals were randomly assigned into seven groups of five animals per group. Group 1 served as control. 10 mg/kg, 20 mg/kg, and 30 mg/kg of quinine were administered to Groups 2, 3 and 4, respectively, every 8 h for 7 days. Groups 5, 6, and 7 received 10 mg/kg, 20 mg/kg, and 30 mg/kg of quinine, respectively, every 8 h for 7 days and were then allowed to recover naturally for another 7 days. The animals in Groups 1, 2, 3, and 4 were sacrificed on the 8th day 24 h after the last administration, while the animals in Groups 5, 6, and 7 were sacrificed on 15th day of the study under chloroform anesthesia. Brain tissues were perfused with phosphate buffer solution, harvested for processing, and stained for histomorphological evaluation. The animals were weighed before the beginning of the quinine and after the completion of administration of the injectable quinine.

The whole brain tissues were fixed in 10% formal saline and then transferred to a graded series of alcohol. The tissues were dehydrated in 70% ethanol for 7 h followed by 90% alcohol overnight and then in three changes of absolute alcohol for 1 h each. The tissues were then cleared in xylene and infiltrated in molten paraffin wax in the oven at 58°C. The tissues were then embedded in wax and blocked out. Serial sections of 5 μ thick were obtained from a solid block of tissues. The tissues were then stained with hematoxylin and eosin staining method after which they were passed through ascending grades of alcohol, cleared in xylene and mounted in DPX mountant, allowed to dry at room temperature, and observed for histopathological findings under a digital light microscope (Cole 1948).


  Results Top


The histopathological evaluations of the IC of the brain of albino Wistar rats are shown in photomicrographs Labeled [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] representing their respective groups as in experimental design. The IC of the control group with no treatment [Figure 1] showed normal histological features with the neurons appearing distinct and conspicuous cellular population with no cytohistomorphological alterations.
Figure 1: Photomicrograph of inferior colliculus from Group 1 rats (control) revealed normal neuronal cell body and neuronal density (H and E, ×400)

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Figure 2: Photomicrograph of inferior colliculus of rats treated with 10 mg/kg of quinine for 7 days (Group 2) revealed neuronal cell degeneration, thickened nerve fibers, and reduced neuronal population (H and E, ×400)

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Figure 3: Photomicrograph of inferior colliculus of rats treated with 20 mg/kg of quinine for 7 days (Group 3) revealed neuronal cell degeneration, thickened nerve fibers, and reduced neuronal population (H and E, ×400)

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Figure 4: Photomicrograph of inferior colliculus of rats treated with 30 mg/kg of quinine for 7 days revealed severe neuronal cell degeneration, thickened nerve fibers, and reduced neuronal density (H and E, ×400)

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Figure 5: Photomicrograph of inferior colliculus of rats treated with 10 mg/kg of quinine for 7 days and withdrawn for 7 days (Group 5) revealed neuronal cell regeneration and better neuronal population (H and E, ×400)

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Figure 6: Photomicrograph of inferior colliculus of rats treated with 20 mg/kg of quinine for 7 days and withdrawn for 7 days (Group 6) revealed neuronal cell regeneration and more neuronal population (H and E, ×400)

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Figure 7: Photomicrograph of inferior colliculus of rats treated with 30 mg/kg of quinine for 7 days with 7 days post quinine administration revealed neuronal cell regeneration, normal nerve fibers, and enhanced neuronal density (H and E, ×400)

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Quinine-treated groups (Groups 2, 3, and 4) that were treated with 10 mg/kg, 20 mg/kg, and 30 mg/kg, respectively, revealed mild-to-severe cytoarchitectural distortion and neuronal degeneration in a manner that were dose dependent. Neuronal cell degeneration and reduced neuronal density were also observed [Figure 2], [Figure 3], [Figure 4]. Seven days after the withdrawal of quinine, there were observable cellular recovery and neuroregenerations in the IC of Group 5 with normal area of neuronal cell and neuronal density [Figure 5], but this was not so pronounced in Groups 6 and 7 [Figure 6] and [Figure 7] 7 days after the withdrawal of quinine treatment.


  Discussion Top


The present study demonstrated that quinine exhibited a deleterious effect on the IC of rats as observed from hematoxylin and eosin staining. Quinine possibly acted as toxins to the cells of the IC, affecting the cellular integrity and causing a defect in membrane permeability and cell volume homeostasis. Quinine is known to cross membrane by simple diffusion, thus getting access to the cells (Lullmann et al. 1978). This must have resulted in the degenerative changes due to oxidative stress observed in this study.

Cell destructions observed in neurodegeneration are caused by neurotoxins which include environmental chemicals and substances also present in cells (Waters 1994). The observed changes in this study are based on the capacity of matured cells to undergo a switch in response to an insult, and it is essentially characterized by upregulation of intermediate filament protein (Nahirnyi et al. 2013).

The greater the severity of insults on the cells, the more rapid the progression of neuronal injuries (Ito et al. 1975; Martins et al. 1978). This explains the dose-dependent severity in the toxicity of quinine observed in this study. The adverse effect of quinine on the IC observed in this study may underline the possible neurological symptoms such as tinnitus as previously reported following administration of quinine (Manolette 2001).

Quinine has also been reported to cause damage to the nervous system (brain and spinal cord) of fetus, inducing bleeding inside the eyes and other problems in animals (Macromedex 2001). Neurotoxins have been reported to induce massive cell destruction and neurodegeneration. Sparse cellular population of IC reported in this study is attributed to cell death caused by the toxic effect of quinine.

The IC is an important processing center in the auditory midbrain and occupies a crucial position in the primary auditory pathway, integrating input from a broad range of auditory brainstem nuclei and relaying information to the auditory thalamus and to nuclei at the sensorimotor interface (Irvine 1992). Cinchonism, characterized by ringing in the ear, headache, and deafness, is a common symptomatic and dose-dependent adverse reactions of quinine (Dorland 2000). The toxicity of quinine on the IC as revealed by this study may be an underlining cause or contributing factor to the general cinchonism associated with hearing.


  Conclusion Top


This study has revealed that quinine is toxic to the IC in a dose-dependent manner and the effect is reversible after withdrawal of quinine for some days.[24]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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