**6.1 Acrylamide induced dopaminergic neuronal loss in rat striatum**

Recent research has revealed that ACR-induced locomotor abnormalities and neurotoxicity are comparable to the effects seen in PD, as ACR can cause key parkinsonian pathology such as α- synuclein aggregation [61]. The prominent hallmark of PD is the depletion of monoamine neurotransmitters (NTs) known as dopamine (DA) and its associated loss of dopaminergic A9 neurons in the substantia nigra pars compacta and striatum [58, 62, 63]. Motor control, cognitive decline, muscular

stiffness, body posture instability, and movement difficulties are symptoms associated with the loss of dopaminergic A9 neurons [62]. DA, a kind of catecholamine, is a NT that governs important functions like cognition, motor control, emotion, and neuroendocrine activity [1, 7, 63]. A massive proportion of DA-carrying nigrostriatal neurons can be found in the striatum, which is the largest integral processing unit present in the basal ganglia [1, 63]. Tyrosine hydroxylase (TH) is a rate-limiting enzyme that is accountable for the synthesis of DA. TH helps to convert tyrosine into 3,4-dihydroxyphenylalanine (DOPA). DOPA is further converted to DA by the action of the enzyme, aromatic amino acid decarboxylase. Cells that are TH-positive are represented as dopaminergic neurons [1, 63, 64]. ACR is most commonly administered to rats either through their oral gavage or through intraperitoneal injection. When ACR is injected in this form, it gets metabolised into GA because of chromosome P450-2E1 present in the liver microsomes. DNA adducts that are formed as a result of the interaction between GA and DNA are responsible for provoking modxicity and carcinogenicity. Since ACR-induced neurotoxicity is strongly associated with the monomer of ACR itself, intracerebroventricular injection aids in transmitting the ACR to the neurons without resulting in the formation of GA. Studies have reported that rats treated with ACR through intracerebroventricular injection have shown a serious decline in the protein expression of TH and the number of TH-positive cells belonging to the striatum [1].

#### **6.2 Acrylamide induced neuronal apoptosis in the rat striatum**

Neuronal apoptosis results in the death of neuronal cells gradually leading to the development of neurodegenerative diseases. Neuronal apoptosis, a definite form of cell death, has a pivotal function in ACR-induced neurotoxicity in rats [65]. Studies have reported that ACR can result in neuronal apoptosis of the striatum. Nissl body is a chromatophilic substance that is very specific and is found in the cytoplasm of neuronal dendrites. Besides protein synthesis, Nissl bodies are crucial for brain functions like memory and learning. Since protein synthesis is essential for proper neuronal function, the presence of the Nissl body is indispensable. Rats treated with ACR reported the presence of pyknotic nuclei and the disappearance of Nissl substance in the striatal neurons. Striatal neurons treated with ACR also appeared swollen with decreased cellular integrity and exhibited an irregular arrangement [60]. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining is generally performed to investigate the loss of neurons due to apoptosis. Recent studies have reported that ACR treatment in rats has significantly raised the levels of TUNEL-positive cells in the rat striatum, which suggests that ACR exposure can result in striatal dopaminergic neuronal apoptosis. Hence, these kinds of studies suggest that ACR can also be a significant environmental risk factor for diseases like PD [1].

### **7. Therapeutic agents against neurotoxicity of acrylamide**

To be able to mitigate the neurotoxic effects of ACR, therapeutic agents of different types are used at different doses. Phytoconstituents have been widely studied for amelioration of neurotoxicity in rats but there are adequate studies on dietary supplements, drugs and probiotics (**Figure 2**).

*Acrylamide: A Neurotoxin and a Hazardous Waste DOI: http://dx.doi.org/10.5772/intechopen.102607*

**Figure 2.**

*Effects of therapeutic agents on neurotoxicity caused by acrylamide.*

#### **7.1 Phytochemicals**

Few phytochemicals are thymoquinone, curcumin and quercetin. The anti-apoptotic property of thymoquinone plays a crucial role in attenuating the toxicity induced by ACR in rats by mitigating oxidative stress, reducing Bax/Bcl ratio, maintaining the integrity of the blood brain barrier (BBB), decreasing the level of caspase 3 and 9 and reducing glial fibrillary acidic protein (GFAP) content which indicates astrocyte damage [41, 66]. Curcumin increased the number of TERT positive cells and decreased the number of TUNEL positive cells in the cortex of ACR treated rats. Additionally, curcumin can also cross the BBB and alleviate spatial memory damage induced by ACR [33, 67]. Quercetin enhanced DA and serotonin levels, reduced biomarkers of oxidative stress, restored acetylcholinesterase (AChE) activity in ACR-treated rats. It can move across the BBB and exhibit its therapeutic efficiency [36, 68, 69]. Other compounds like metformin, minocycline and zolpidem also show similar therapeutic effects to dietary supplements when administered to ACR-treated rats [70–72] (**Table 2**).

#### **7.2 Drugs and supplements**

Vitamins have shown therapeutic effects when administered to ACR-induced rats by ameliorating their toxic effects. Vitamins like vitamin E, vitamin F, vitamin C and vitamin B6 have been studied for their ameliorative property on rats influenced by ACR neurotoxicity [37, 74, 75]. They are widely known for their powerful antioxidative property and are also used as positive control groups while evaluating the potential of other therapeutic agents against ACR toxicity in rats [41, 80]. Vitamin E is phospholipid soluble and a neuroprotective antioxidant. It elevated brain-derived


#### **Table 2.**

*Therapeutic agents that attenuate acrylamide neurotoxicity in rats by different methods of exposure at various doses and times.*

neurotrophic factor levels and lessened oxidative stress through its sweeper effect and removed free radicals in the brain tissue of fetal rats [49]. It also attenuated inflammation, apoptosis and behavioural neurotoxic effects in rats [37, 73]. Linoleic Acid (LA) is an essential omega-6 fatty acid with antioxidative, anti-inflammatory and neuroprotective effects [75]. LA improved ACR oxidative effects by restoring the activities of antioxidant enzymes, reducing the generation of free radicals, preventing LPO and obstructing genotoxic damage by reducing GA. AchE activity was also ameliorated by restoring vacuolization loss by pyramidal cells and Purkinje cells [75]. Vitamin B6

*Acrylamide: A Neurotoxin and a Hazardous Waste DOI: http://dx.doi.org/10.5772/intechopen.102607*

was also able to attenuate the intensity of ACR effects by increasing the availability of energy to the neurons [81]. When administered to pregnant rats vitamin C lessens the effects in white matter volume, the volume of the cerebellar cortex, molecular and granular layer volume and cerebellum damage [74]. Omega-3 fatty acids have also been studied as a therapeutic agent that can attenuate neurotoxicity caused by ACR in rats. Fish oil was able to reduce the neurotoxic effects evoked by ACR in rats. It restored oxidative stress by improving MDA, GSH, LPO, protein carbonyl content, free radicals and antioxidant status [65, 76]. Omega-3 Polyunsaturated fatty acids (PUFAs) regulate neurotransmission by modulating the activity of NTs. They also attenuate apoptosis by increasing anti-apoptotic BCL-2, expressing Hsp27 and inducing oligodendrogenesis [77]. Fish oil mitigates inflammation and astrogliosis by reducing inflammatory cytokines and GFAP positive cells [76]. Melatonin (MT) alleviates DNA damage, levels of MDA, SOD, GSH-Px, GSH and nucleus concentration [34, 78]. It relieved weight loss and gait abnormality. MT shows an increase in the levels of brain NTs and a reduction in AchE activity, serum tumour necrosis factor (TNF)—α and cortical amyloid protein levels [79]. MT treatment restored ACR evoked oxidative stress by down-regulating Nrf2, nuclear factor kappa B (NF-kB) and Kelch-like ECH-associated protein 1 (Keap-1) activity (**Table 2**) [78].
