Volume 8, Issue 6, June 2023 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165

Animal Models for CNS Disorders:

Current Perspectives and Future Directions
Tejesvi Mishra*
National Coordination Centre for Pharma covigilance Programme of India,
Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Ghaziabad, India

Abstract:- The numbers of probable neurotoxins are contaminated with Clostiridumperfrigens, a spore forming
rising day by day and pose a perilous neuro- bacterium potentiate chances of multiple sclerosis. Exposure
inflammation to the body. Currently, the evaluation of to neurotoxins like dithiocarbamate (DTC) induces
neurotoxicity is the most accomplished assessment in Parkinson disease (PD), also known as “shaking palsy”;
non-clinical as well as clinical studies. Mislaying which itself is a complex progressive neurodegenerative
memory, frailty in body, clouded vision, headache, and disorder leading to the degradation of dopaminergic neurons
psychological un-certainty subsequently developing [3]. Alzheimer’s disease denotes loss of memory due to
cognitive puzzlement are some of the major signs of imbalance in between acetylcholine and dopaminergic
progressive inflammation in brain. Asserted evidence in neurons. Although this disorder usually shows association
research states that the activated microglia, a major part with old age and genetic factors, exposure of microbial
of brain causes damage to the neurons present in central toxins such as bacteria, molds and viruses may contribute to
nervous system. The pattern of over-activated microglial cognitive declines [4]. An abnormal electrical activity in the
cells followed by oxidative stress found to be the main brain that stimulates recurrent seizures is referred to as
pathway involved in neurotoxicity. Many studies Epilepsy. [5] It was found that this induction of seizures is
support the involvement of reactive oxygen species sometimes associated with exposure of certain pesticides
(ROS) generation in hippocampus leading to toxic including parathion and carbaryl. One of the evident motor
mediator’s release and suggest excitotoxicity involving neuron diseases (MND), frequently found in adults is
overload of Calcium ions in frontal cortex as a secondary Amyotrophic lateral sclerosis (ALS). It is progressive as
damage. With the evolution of animal model, there has well as fatal and shows its symptoms twitching of muscle,
been research-based analysis which affirms that a fatigue, difficulty in swallowing and shortness of breath,
developmental inflammatory symptom in brain can be after the exposure of soil related fungal toxins [6]. As soon
induced by several drugs, chemicals, pesticides and can as chemicals like phenol and gases like hydrogen sulfite is
lead to neurodegenerative disorders. This study indulges exposed, there is a lack of blood flow in brain that results in
with a descriptive remark on various rodent models stroke causes by formation of clot or direct blockage in
related to neuronal inflammation. arteries. Weakness followed by numbness in muscles,
improper speech, imbalance and blurred vision are
Keywords:- Heavy metals; Pesticides; ROS; Hippocampus; symptoms of stroke [4] and [7]. These neurological
Neurotoxicity; Neurodegenerative diseases. disorders are becoming much more vulnerable now a days.
World wide data of world health organization (WHO)
I. INTRODUCTION report, 2021 suggests that, across the globe 30 million
The Society of neuroscience, 2012 [1] states that the people are suffering from neuronal diseases that are
nervous system is a complex and highly specialized network somehow subjected through neurotoxicity. In India,
and functioning. From vision to olfaction; walking to population survey summarizes the incidence and prevalence
sleeping and speaking to thinking, our system of neurons rate variation according to regions of the country. In a recent
organizes, explains and connects to perform actions. This data it was found that, the cases of this neurological disease
nervous system comprises several parts including the brain, was found more in men as compare to women but women
spinal cord and nerves to connect them. According to have high mortality rate [8]. When neurodegenerative
(National Institute of Neurological Disorder, 2018), any disease comes into picture, neurotoxicity is claimed to be
abrupt ingestion or exposure of toxins (natural, chemical, one of the major reasons. Neurotoxicity as the name itself
heavy metal, trauma, injury or certain drugs like suggests, it is toxicity associated with neuronal regions
cyclophosphamide and cefepime) may results in neuronal present in body [9]. The toxicity could be induced in brain
toxicity due to disruption of neurons. According to the study or in the whole peripheral region of the body as neurons are
of [2] the first and foremost symptom of neurotoxicity present everywhere in the body [10]. The pathological
targeted to the brain denotes headache. Headache is one of changes such as oxidative stress, microglial activation
the most common neurological disorders that affect anyone followed by neuronal inflammation due to neurotoxicity can
at any age. Association of headache with fever, photo- occur from exposure of several neurotoxins [11]. These
sensitivity followed by stiffness of muscles predicts signs of neurotoxins (including heavy metals like arsenic, mercury
meningitis. On the contrary, chronic pain in one portion of and lead; chemicals like alcohol and phenol derivatives and
the head may signify migraine. As per (American Society of carbofurans) are the particular agents that have ability to
Microbiology, 2014) Multiple sclerosis (MS) is a kind of stimulate the inflammation in neurons [12]. The prognosis
neuronal inflammatory disease characterised by disruption of brain toxicity is always known to be related to the length
of blood brain barrier and demyelination. Ingestion of food and degree of exposure in contrast to the severity of

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 Volume 8, Issue 6, June 2023 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
neurological injuries. As per study of [2], it has been found V. MORRIS WATER MAZE TEST
that at a specific level the exposure of neurotoxin can be
fatal but in some cases patients may completely be able to According to [21], this model helps to understand
recover after the required treatment [13]. Exposure of spatial learning ability of rats. Within a circular tank divided
neurons to neurotoxins can also leadto cause progressive into 4 quadrants, filled with water in a depth of 20 cm rats
neurodegenerative diseases like Parkinson’s disease, are placed. Rats learn to swim in water tank to escape
Alzheimer’s disease, Huntington’s disease and disorders like platform hidden under water. Rat has to find the platform to
meningitis. In prognosis of such diseases, there is always escape within 15 minutes. Trained rats and rats with good
involvement of neuronal inflammation and oxidative stress memory used to take time of less than 10 seconds. This test
generation at neuronal site. These neurotoxic effects can be helps in assessment of memory as well as learning ability of
studied well with the help of various toxicological models rats. Complex procedure and handling assessment can be its
[14]. Experimental studies explained below are helpful to demerit [22].
analyse chronic outcomes on brain.
VI. TREMORINE AND OXOTREMORINE
II. ELECTRIC SHOCK SEIZURES IN RODENTS ANTAGONISM

As per [15], An Electric shock induced seizures in The rationale of this study is to reduce Parkinson’s like
mice and rat model signifies development of epilepsy. In symptoms (including tremor, ataxia, salivation, lacrimation,
this model seizures are potentiated by applying electric and spasticity) in rodents by administration of muscarinic
shock of 60 micro ampere, 60 hertz for 2 seconds on rat. On antagonists (like tremorine and oxotremorine). Animals are
the contrary, 12 microampere with a frequency of 50 hertz is administered with a dose of 5mg/kg benzatropine 1 hour
applied in case of mice for 0.2 seconds. Due to electro- prior administration of 0.5mg/kg oxotremorine via
convulsive shocks, inflammation followed by destruction of subcutaneous route. Score of tremors, salivation, and
neurons occurs leading neurological disorders like epilepsy. lacrimation is recorded under 3 observations. This model
This model predicts more accurate results but, physical measures only central anti-cholinergic activity, and it is not
instability of rodents become one of the demerit of this used for assessment of dopaminergic drugs [23].
model. This study is more prone to brain traumatic injuries
[16]. VII. RESERPINE ANTAGONISM

III. KINDLING RAT SEIZURE MODEL The purpose of this test is to analyse sedation in mice,
as reserpine induces depletion of central catacholamines.
This model summarizes repetitive administration of an Due to sedative effect, mice are observed with signs of eye
initially sub convulsion electrical stimulation on rodents. lid pitosis, hypokinesia, rigidity, and immobility. In this
Electrodes are re-implanted in right amygdala of brain by study, preferably male mice are administered with reserpine
surgical method and stimulations are provided. Animal is (5mg/kg) intra-peritoneal route and tested after 24 hours.
then allowed to recover from surgery for at least 1-2 weeks. Before 30 minutes of observation, administration of test
Daily electrical stimulations are applied via electrodes (400- compound is done. Evaluation of loco motor activity such as
500 micro ampere for 1 mili second). Animals are tested on rearing and grooming are scored. This model shows
the day, before and after the treatment of test compound significance in assessment of loco motor activities as well as
[16]. Occurrence and degree of seizures are compared behavioural studies [24].
between control and test compounds. Kindling rat model
provides effect of reoccurrence of electric shocks on brain. VIII. N-METHYL-4-PHENYL-1, 2, 3, 6-
In comparison Electric shock model, this study has more TETRAHYDROPYRIDINE (MPTP) MODEL
chances to develop trauma in rodents as there is re- FOR RODENTS
occurrence of electric shocks [17]. N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
(MPTP) itself act as a neurotoxin that usually destruct
IV. RUN WAY AVOIDANCE IN RATS AND MICE
dopaminergic cells present in substantianigraof brain results
In this model analysis, animal is placed in the box with occurrence of Parkinson’s like symptoms. A dose of 5-9
uniform illumination of light. One loud speaker is also mg/kg via intra peritoneal route is administered in mice for
mounted 50 cm above the start box. The animal is 5-8 days followed by test drug. Locomotion, sleep duration,
administered acoustic stimulus of 80db of 2000 hertz balance and coordination are evaluated and scored [25].
frequency. After 5 minutes animal is exposed to electric MPTP model shows contribution in analysis of Parkinson
shock of 1 micro ampere for 1 second [19]. Thereafter, like disorder in not only rodents but also in monkeys. This
evaluation of time required to reach safe at door is noted in study can also be helpful in summarizing effect of
order to access the efficacy of drug. It is one of the simplest neurotoxin in various CNS disorders including depression
study for assessment of behavioural studies [20]. and anxiety in which dopamine plays vital role. Exposure to
neurotoxin can also cause lethal effects in brain, sometimes
can be fatal for animal [26].

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Volume 8, Issue 6, June 2023 International Journal of Innovative Science and Research Technology
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IX. VARIOUS ANIMAL MODELS FOR defining executable health risks and rectifiable
NEUROTOXICITY Neuropathological processes &inflammated neuropathy in
the brain, notably in the hippocampus region, was
A study at genetic level was conducted to analyse discovered to be a main cause of inflammated neuropathic
synucleinopathy induced neurotoxicity in rodent cells. pain in a mouse model where this psychotic disease was
Leucine-rich repeat kinase-2 (LRRK2) causes microglial created. [22], [29]. AD is one of the well-known
cells to get stimulated in response to raised extracellular α- neurological disorders that can be specified by defienciency
synuclein results in neurotoxicity [27]. Induction of sepsis of dopaminergic neurons which is always marked for
in brain via cecal ligation and puncture (CLP) in rodents depletion of neuronal networks in brain. In a study AD was
results in down-regulated expression of interleukins (IL-1β, induced in rodents via intra-cerebroventricular implantation
IL-6), and tumor necrosis factor (TNF-α) followed by long- and cannulation in brain that leads to hyperactive neurons
term cognitive impairment [18], [27]. In neonatal mice, high and altered functioning followed by inflammation [6], [29].
quantities of pain killers such as sevoflurane, isoflurane, and Anxiety is characterised by feelings of fear, dread, and
midazolam were reported to cause altered learning and uneasiness, as well as nervousness, restlessness, a sense of
memory abnormalities Parkinson’s disease exacerbates α- approaching danger, and panic. It can make you tired, feel
synuclein in brain which directly indicates neuronal uneasy and tight, and cause your heart to race. It's possible
inflammation. As PD itself is a neurodegenerative disorder, that it's a natural reaction to stress. Anxiety was produced in
therefore its lethal effects may summarize the key features mice by exposing them to a dark room for two weeks in a
of neurotoxic mediators like longterm memory deflects murine model research. Rodents were shown to have a lower
followed by improper release of motor hormones in rodent level of social interaction [14], [30]. Neuroinflammation can
model [15], [28]. Ischemia is marked for decreased level of also be produced by induction of microelectrodes in brain
oxygen in the cell, but when the oxygen amount is less in via intra cortical implantation. In a pre-clinical study of
brain cells it leads to generate acute ischemic stroke. Due to similar model when the surgery was performed, there was a
which there is decrease in brain water content followed by rise in inflammatory biomarkers, toll-like receptors (TLR)
lipid peroxidation and inflammation [29]. Schizophrenia is a followed by neuronal astrocytes activation. [23], [31].
complex psychotic ailment with unidentified etiologies and Excitotoxic Injury induction in mice also leads to cause
inadequate treatment options. Recent developments in lethal neurotoxicity in hippocampus and frontal cortex of
understanding both hereditary and hormonal impacts on risk brain.
for this condition have given rise to a lot of optimism in

Table 1: Disorders of CNS caused by neurotoxicity

CNS disorder caused Species Dose and route Duration Observations References
by neurotoxicity

Sepsis Old Sprague- Intracerebral implantation Treatment Down regulation of IL-1β, [18]
Dawley rats drug 14 IL-6, and TNF-α.
days

Parkinson’s disease C57BL/6 2.5 mg/kg by 36 days Microglial activation [15]

mice intracerebroventricular Dopaminergic neuro-
injection degeneration

Acute ischemic stroke Mice Middle Cerebral Artery Astrocyte-mediated [21]

Occlusion-Reperfusion inflammation
(MCAO/R) surgery ROS generation
Lipid peroxidation

Over dose of C57Bl/6 3% isoflurane: 2 hr/day 3 days Cognitive defects [6]

Anaesthesia in mice neonatal altered memory
mice

Oxidative injury C57BL/6 Surgery of cortex Release of inflammatory [42]

induced neurotoxicity mice bio-markers

Schizophrenia Transgenic Induction of 22q11 deletion 2 weeks Hippocampal [22]

mice syndrome (22q11DS) hyperactivity and
Psychosis-related
behaviour

AD induced APP/PS1- Surgical 6 weeks Astrocyte-specific deletion [6]

neurotoxicity Stat3WT Intracerebroventricular of Stat3

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mice implantation Dystrophic neuritis

Inflammation in frontal
cortex of brain which is
responsible for learning
and memory.

Anxiety induced Mice Dark exposure to mice 2 weeks Reduced social interaction [14]
neurotoxicity Hippocampal oxidative
stress

Implanted C57-BL6 Surgical implantation Up-regulation of toll-like [23]

microelectrodes induced mice Intracortical microelectrode receptor (TLR-4) and
neurotoxicity catalase
Activated macrophages
CD68
Neuronal nuclei damage

A. Pesticide induced neurotoxicity illness, neurodegenerative diseases (Alzheimer's disease,

Pesticides are designed to kill bugs, but they can be Parkinson's disease, and amyotrophic lateral sclerosis), long-
harmful to the brain. In addition to CNS impacts, their term neuropsychiatric effects of acute and repeated
exposure can cause a variety of neurological problems by exposures such as acetylcholine receptors inhibition,
acting on synapses, such as a sodium/potassium mismatch, astrocyte deficits, oxidative stress and neuroinflammation,
which prevents normal nerve impulse transmission. They and autoimmunity, and long-term neuropsychiatric effects of
disrupt neurological signals by sinus inflammation, acute toxicity [34]. Numerous neurological illnesses have
disorientation, and chest pain, followed by severe muscle been linked to exposure to the fungicide ziram (zinc
aches [32]. Organophosphorus (OP) cholinesterase inhibitor dimethyldithiocarbamate). In rodents, ziram administered
intoxication can cause convulsions that can result in long intranasally produces neurochemical changes. In findings of
consequences. A preclinical paradigm in which acute di- [35], Inflammatory mediators including TNF-α causes
isopropylfluorophosphate (DFP) intoxication results in cellular damage in brain that provokes the release of 4-
tremors, ongoing cytokine production, death, and cognitive hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NTS) in the
problems due to neuronal injury and neuro-inflammation striatum region. Carbofuran is a chemical pesticide that is
caused by gliosis which is known for enlargement of glial widely used to manage insects as well as nematodes during
cells. As glial cell plays a key role in adapting inflammation crop production due to its biological activity. It also acts as a
in the neuronal region by direct stimulation of cellular neurotoxin that induces neurotoxicity by generating free
responses in neurons, astrocytes and blood brain barrier radicals and depletion of critical antioxidant enzymes, as per
followed by T-cells infiltration [33]. Organophosphates World Health Organization (WHO). The modification of
(OP) are a group of compounds that are phosphoric, acetylcholine-esterase (AChE) and other transporters has
phosphonic, and phosphinic acid derivatives. The severe been linked to carbamate-induced cytotoxicity.
effects of OP can lead to severe problems such as aerotoxic

Table 2: Pesticides induced neurotoxicity in rodents

Name Species Dose and Duration of Findings References

route of experiment
adm.

Acute Sprague 9 mg/kg 14 days Acute DFP intoxication causes [17]

diisopropylfluorophosphate Dawley rats persistent neuronal damage and
(DFP) neurotoxicity neuroinflammation, cognitive
deficits

sodium Swiss Intranasal 7days Depression like behavioral [8]

dimethyldithiocarbamate albinoMice alterations
induced neurotoxicity 10 μL, 100
mg/mL Activated astrocytes

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carbofuran-induced Swiss albino 5 mg/kg 90 days Change in antioxidant markers [21]

neurotoxicity mice b.wt/ day

From the above explained table; Acute- [36] indicated induction of the MAPK p-P38/p-JNK
diisopropylfluorophosphate (DFP) neurotoxicity model can pathway, triggered gliosis, productive p-NF-KB/p-IKK,
be utilized for neurodegenerative disorders like Alzheimer apoptosis, and neuro degeneration. The NF-kB/Nrf/HO-1
disease, Parkinson’s disease while sodium propagation pathway was discovered to be involved in stress
dimethyldithiocarbamate can be utilized in models for and alcohol-exposed rodents in a study. Chronic immobility
depression. and alcohol intake can result in harmful consequences in the
hippocampus area of the brain, which can lead to cognitive
B. Chemicals induced neurotoxicty impairment [37]. Due to administration of 3-nitro propionic
There are various chemicals those have deleterious acid (3-NP), lipid peroxidation and alteration in motor
effects to central nervous system (CNS) such as alcohol activity was noted [38]. When it comes to neurotoxicity,
based products and phenolic compunds. Acute ethanol hydrogen sulphite is the most common neurotoxic gas, and
treatment to postnatal pups causes significant its exposure results in changes in neurotransmitter like
neurodegeneration, and studies have demonstrated that the dopamine levels in brain which leads to altered behaviour of
neurotoxicity generated in the neurodevelopment can last for rodents [39].
a lot longer, even into adulthood. Upon administration of
high dose of ethanol in rats, the cellular level findings of

Table 3: Chemical-induced neurotoxicity in rodents

Name Species Dose and route of Duration of Findings References

adm. experiment

Ethanol induced Sprague single dose of acute 7 days Activation of the MAPK p- [24]
neurotoxicity dawley rats ethanol (5 g/kg, P38/p-JNK pathway, activated
pups subcutaneous (s.c.) gliosis, and neuronal
degeneration

Alcohol induced Swiss 15% v/v oral 28 days Activated p-NF-KB/ p-IKKβ, [12]
neurotoxicity albino mice apoptosis

3-nitropropionic acid Wistar rats 30 mg/kg, i.p. 22 days Stratum damage in brain [11]
induced
neurotoxicity

From the above explained table; ethanol induced stimulating the CNS with medications has always resulted in
neurotoxicity can serve as model for neuro-degenerative a significant increase in neurotransmission signalling in the
diseases like Alzheimer disease, Parkinson disease and brain. According to a recent study, CNS stimulants produce
epilepsy. As rising evidence shows that depression may a rise in serum and brain levels of lipopolysaccharide (LPS)
results in neurodegenerative disorders, therefore ethanol and brain cyclooxygenase-2 (COX-2). Studies have reported
exposure at 5mg/kg via subcutaneous route may provoke that regular administration of Methamphetamine caused
neuronal destructive diseases. dopamine and serotonin in the brain striatum, there is a
shortage of dopamine and serotonin in the striatum, along
C. Drug induced neurotoxicity with serotonin in the prefrontal cortex, due to regular
Docetaxel (DTX) is a chemotherapeutic drug that is used administration of methamphetamine [41]. 2C (2C-x) , one of
to treat a variety of cancers. However, it causes CNS the most common chemicals from the family of
deflicits. In DTX-induced rodent models, abnormal levels of phenethylamines with two methoxy groups 2 and 5 positions
glutathione (GSH), superoxide dismutase (SOD), catalase in benzene ring have potential to produce neurotoxic effects.
(CAT), and glutathione peroxidase (GPx) were discovered. Activated microgliosis, increased both Iba-1 and GFAP
Other findings include decreased c-Jun N-terminal kinase expression levels in the striatum were also noted [42]. In
(JNK) expression in the sciatic nerve and higher cyclic AMP Pentylenetetrazol (PTZ)-kindled model; mice were
response element binding protein (CREB) expression in the acclimatised and confronted to an electroconvulsive shock
brain, most of which were stimulated by DTX [40]. Over- of 12 micro ampere, 50 hertz of frequency for 0.2 seconds,

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2-3 times per week for a duration of 28 days; then studied medicine that is routinely used to treat a variety of
for excitotoxicity and inflammation in central nervous haematological malignancies; nevertheless, neurotoxicity in
system [43]. An administration of 5-FU in rodents at a high rodents is a typical repercussion. Vincristine was discovered
dose can lead to convulsions, tremors, confusion and to have the potential to cause ganglionic and neurological
memory memory impairments. Vincristine (VCR) is a abnormalities in a recent pre-clinical research [44].

Table 4: Drug-induced neurotoxicity in rodents

Name Species Dose and Duration of Findings References
route of adm. experiment

Vincristine-induced C57BL/6 J 0.1mg/kg ip 14days Hyperalgesia neurite damage [26]

neurotoxicity mice ganglionic damage

5-FU induced neurotoxicity Swiss albino 200 and 400 14 days Convulsions [17]
mice mg/kg, i.p. Tremors confusion

PTZ (pentylenetetrazol) Swiss albino PTZ (40 mg/kg, 5 days per week Generation of reactive nitrogen [18]
induced neurotoxicity mice i.p.), for 13 days species (RNS) and
inflammosomes

Phenethylamines induced C57BL/6 J 10 mg/kg i.p. 7 days Reduced motor activity [19]
neurotoxicity mice induce memory defcits

Methamphetamine induced Sprague 10 mg/kg, once 28 days Raised level of Calcium, [25]
neurotoxicity Dawley rats every 2 hr via glutamate-mediated
i.p. excitotoxicity

Docetaxel-induced Sprague a single dose of 7 days Reduced level of glutathione [2]

neurotoxicity Dawley rats DTX (30 (GSH), superoxide dismutase
mg/kg, b. w.) (SOD), catalase (CAT) and
i.p. on 1st day glutathione peroxidase (GPx)
Altered expression of nuclear
factor erythroid 2-related factor
2 (Nrf2), heme oxygenase-1
(HO-1) and B-cell lymphoma-2
(Bcl-2) and downregulated the
expression of Bcl-2 associated
X protein (Bax)

Cefepime induced Swiss albino 250 and 14 days Raised level of inflammatory [26]
neurotoxicity mice 500mg/kg i.v. biomarkers in brain like IL-8
and IL-12

From the above explained table; 5-FU induced X. HEAVY METALS INDUCED
neurotoxicity and Methamphetamine induced neurotoxicity NEUROTOXICITY
can be treated as models for epilepsy. Phenethylamines
induced neurotoxicity, Cefepime induced neurotoxicity and Heavy metals are well known for their deleterious
PTZ (pentylenetetrazol) induced neurotoxicity can serve as effects in the body. Although the effect of heavy metal has
models for Alzheimer’s disease and Parkinson disease. studied well on vital organs like liver, kidney and gastro-
Docetaxel-induced neurotoxicity and Vincristine-induced intestinal tract (GIT), though some studies like [45] have
neurotoxicity can be utilised as models for other reported about their effect on the central nervous system
neurological disorders including Amyotrophic lateral (CNS). Lead poisoning causes not only perinatal toxicity but
sclerosis (ALS) and multiple sclerosis (MS) and also brain diseases, including learning and memory
Huntington’s disease. impairment. In aged rats, lead exposure causes cognitive
impairment by altering intracellular calcium signalling via
RyR. There is a promotion of inflammation and cell
oxidation buildup of lead in tissues [46]. In mice, mercury
sulphite causes chronic neuro inflammation, which is
followed by impaired body movements, increased microglia
activation, and consequently death of dopaminergic
neurons.Aside from that, the alteration of the gut

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microbiome utilising real-time PCR with 16S rRNA primers molecule which is used in cancer therapy causes
was also noted [47]. From years, arsenic has been utilised as hyperexcitability of neurons in brain which results in
a homicidal agent. It produces toxic results in brain via chronic neurotoxicity [49]. Manganese (Mn) overdose
reduction of glutathione through methylated oxidation affects the central nervous system, primarily impacting
mechanism [48]. On the other hand, arsenic also reduces nigrostriatal cortical connectivity and resulting in
level of acetyl cholinesterase in brain due to which behavioural and motor disorders due to protein misfolding
neurodegenerative disorders like Alzheimer’s disease get which including -synuclein and amyloid [50].
more triggered. Cisplatin as a first platinum-derived

Name Species Dose and route of Duration of Findings References

adm. experiment

Pb induced Old Sprague 0.05% lead acetate 3 weeks Cell apoptosis, calcium [21]
neurotoxicity Dawley (SD) p.o. overload in cells
rats

hydrogen sulfide– Mice 765 ppm H2S for 1 week Activation of cytochrome [11]
induced neurotoxicity 15 min/day oxidase enzyme
changes in dopamine (DA)
and its metabolites,
Altered GABA/Glutamate

Mercury sulphide C57BL/6 mice 0.6g/kg oral 35 days LPS aggravated MPTP [28]
induced neurotoxicity feeding neurotoxicity
Loss of dopaminergic
neurons

Arsenic induced Male Mice 2 mg/kg 12 days Mitochondrial dysfunction [27]

neurotoxicity Lipid Peroxidation
increased Calpain
Decreased
Acetylcholinesterase Activity

Platinum induced Mice 16 to 80 mg/kg ip 30 days Exaggerated neurons

neurotoxicity Rise in malonaldehyde [16]
(MDA)

Oxaliplatin induced Wistar rats 5mg/kg, was 8 days Destructed α-synuclein and [16]
neurotoxicity administered i.v. amyloid protein
Table 5: Heavy metal-induced neurotoxicity in rodents

XI. CONCLUSION  Conflicts of Interest: Author declares no conflict of

interest
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