الفهرس 
ACKNOWLEDGMENTOnly 14 pages are availabe for public view
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Abstract
The cerebellum is situated in the posterior part of the skull dorsal to the brainstem. It is connected to different parts of the brain stem by three paired cerebellar peduncles. The mammalian cerebellum is divided into two hemispheres and a narrow midline zone (the vermis) and consists of three lobes; an anterior lobe, a posterior lobe, and flocculo-nodular lobe.
The cerebellum is formed of outer gray matter (the cerebellar cortex) and central white matter. The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, in the middle lies the Purkinje layer and in the top lies the molecular layer.
The most important neurons of the cerebellar cortex are the Purkinje and granule cells. The Purkinje cell is the major functional unit of the cerebellum. The Purkinje cells are large cells situated between the granular cell layer and the molecular layer of the cerebellum.
The granule cells are small neurons. They form a distinct layer between the white matter and the Purkinje cell layer in the cerebellum.
The cerebellar cortex contains other neurons rather than the granule cells and Purkinje cells called the satellite cells in addition to the glial cells.
The white matter is sometimes called the arbor vitae because of its branched shape . It is made of largely myelinated nerve fibers
In rat, the cerebellum was first identified as a pair of thickenings on the lateral site of the alar plate of the hind brain vesicle with appearance of the germinal triagone which is the source of the cells of the external granular layer at the13th prenatal day.Then these two thickenings spread medially and reached the midline on day 16 prenatally. The primitive cerebellar cortex bridged the midline at day 17 prenatally. the external germinal layer spread over the surface of the cerebellum at day 17 prenatally. The Purkinje cells are generated between days 13 and 16 with a peak on day 15 prenatally. Deep nuclear neurons begin to differentiate on day 13 prenatally, with two-thirds forming on the day 14.. After the 17th day prenatally.
The cerebellum of newborn rat consists of gray and white matter with primitive folds and fissures. The cerebellar cortex is formed of two layers which are mainly the external granular and thin Purkinje layers. At postnatal day 7, the folds and the fissures of the cerebellum become prominent than the new born and the folds have a prominent external granular layer. Also at this age, the apparent molecular layer is formed between the Purkinje cell row and the external granular layer and reach the maximum thickness at day 23 postnatally. The Purkinje cells in the rat are arranged in several layers at postnatal day 5 and in one layer at postnatal day 10. The granule cells are formed in the second and third postnatal weeks. It becomes clearly differentiated at postnatal day 14. The cell migration has completed and the adult like lamination of the cortex is evident after three postnatal weeks. Tramadol is cis-2-dimethylamino methyl-1-3-methoxyphenyl-cyclohexanol hydrochloride. Structurally, tramadol closely resembles codeine. Tramadol is a weak μ-opioid receptor agonist. Tramadol is an analgesic drug used to treat moderate to severe pain. Tramadol abuse is becoming increasingly more popular among male and female teenagers The prenatal tramadol administration decreases the expression of Amyloid Precursor Protein (APP) which plays a major role in neuronal survival. Tramadol also provokes oxidative stress in the cerebellum and produces an inhibition of the antioxidant enzymes of the mitochondria of the cerebellar neurons that leads to the generation of reactive oxygen species that cause damage of the cellular structures. Tramadol uptake causes an excessive expression of the inducible nitric oxide synthytase (iONS) and though an excessive production of nitric oxide which at a low concentration plays a unique role in neurotransmission and vasodilatation, whereas at higher concentrations, it is neurotoxic. Thyme is an aromatic native herb in the Mediterranean region. It is widely cultivated as spice, tea and herbal medicine. Thyme possess various beneficial effects, like antiseptic, antimicrobial, bactericidal, anthelmintic, antioxidant properties and enhances the blood circulation. The aim of the present work was to study the effects of maternal tramadol administration during pregnancy and lactation and the possible protective role of thyme on the development of the cerebellar cortex of their offsprings. A total number of 48 adult females were used in this work. They were divided into three groups, group I (control group), group II (tramadol group), group III (combined tramadol and thyme group). The female albino rats in the period from day one of pregnancy till weaning and also the offsprings of these pregnant female rats after weaning till adult age. In the experimental group IIpregnant females and their offsprings after weaning were given tramadol HCL (40 mg/Kg body weight/day for 8 weeks for each) suspended in the tap water through gastric tube. In the experimental group III pregnant rats and their offsprings after weaning were treated with tramadol HCL (40 mg/Kg body weight /day for 8weeks for each) and thyme extract (500 mg/kg body weight/day) suspended in tap water, orally through gastric tube. The studied ages in this research were embryos of gestational days 13,16,19 and postnatally newborn, 10 days, 20 days and adult age. Histological techniques were used. Light microscopic study used gallocyanin chrom-alum stain. Electron microscopic study and immunohistochemistry were done. In addition morphometric study regards the number, longitudinal diameter and surface area of the purkinje cells, the density of the granule cells and the thickness of the layers of the cerebellar cortex were measured in all the studied groups using image analysis system and were statistically analyzed The control group revealed in gestational day 13, the cerebellum is formed of a primordium that was covered by the ventricular zone of the cerebellar plate which gives rise to neuronal precursors of Purkinje cells. At this age there is the first evidence of the germinal triagone. In gestational day 16, the germinal triagone enlarges and provides the external granular layer cells. The purkinje cell plate appeared well organized. The choroid plexus becomes slightly aroborized. In gestational day 19, the length of the germinal triagone is reduced and the external granular layer covers the whole surface of the cerebellum. The external granular and purkinje cell layers were formed of multiple strata .The Purkinje cell layer is distinct from the cerebellar medulla. The villi of the choroid plexus become more aroborized. The foliation of the cerebellar surface start to appear. In the newborn age, the cerebellar cortex is differentiated into four layers; external granular layer, molecular layer, purkinje layer and less developed internal granular layer which couldn’t be distinguishe from the underlying white matter. The external granular layer is thicker than the internal granular layer and It is composed of closely packed oval or round-shaped neurons. The molecular layer appeared as a narrow strip. The Purkinje cell layer is localized on the outer peripheral region of the internal granular cell layer and composed of primitive two cell-layers thick. Each cell layer is composed of a large round-shaped cell with a prominent centrally located nucleus. The internal granular layer was less developed. It was formed of variable migrating less differentiating neurons. In the postnatal 10th day, the thickness of the external granular layer is decreased, the thickness of the molecular layer increased and formed of satellite and basket cells. The Purkinje cell layer was arranged in a single row. The Purkinje cells showed an obvious increase in size of their cell bodies. In between the purkinje cells, the glial cells are present. The internal granular layer becomes fully developed . It is formed of closely packed oval-shaped neurons In postnatal day 20, the external granular layer disappeared. The Purkinje cells attained much more growth and differentiation in the cell body size and shape. The internal granular layer was formed of densely packed oval-shaped neurons. The white matter is located in the middle of the folia . In the adult age, the cerebellar cortex is formed of well differentiated three layers, the molecular, the purkinje and the internal granular layers By electron microscopic method, the Purkinje cells of the different studied ages had a large nucleus containing a prominent nucleolus. The purkinje cell perikaryon contained the usual cytoplasmic organelles as round or sausage-shaped mitochondria, rough endoplasmic reticulum and free ribosomes. The cell membrane had multiple synaptic spines in contact with the glial cell processes. The cell bodies of the granule neurons was polygonal in shape. The nucleus of the granule cell contained peripheral clumps of condensed chromatin and is surrounded by a thin shell of cytoplasm. The rosette of the granule cells which contains mitochondria, endoplasmic reticulum and numerous secretory vesicles were noted. Myelin sheath was observed in the neuropil between the granule cells By morphometric study, the mean of the surface area and the longitudinal diameter of the purkinje cells increase from the newborn age to the adult age. The mean number of the purkinje cell decrease gradually from the newborn age to the adult age. The mean density of the granule cells increased gradually from the newborn to the adult age. The external granular layer decreased in mean thickness in the 10th day postnatal than the newborn age and start to disappear at the postnatal 20th day. The mean thickness of the molecular and the internal granular layers increased gradually from the newborn to the adult age. The mean thickness of the Purkinje layer reaches the maximum at the postnatal 10th day then decreases again The embryos and pups of the tramadol group of all the studied ages showed manifestation of developmental impairment of the cerebellar cortex as the retardation of the arborization of the choroid plexus, foliation pattern of the cerebellar surface and time related continuity of the external granular layer in the prenatal ages, the increased thickness of the external granular layer in the newborn and the postnatal10th day and the persistence of this layer in the postnatal 20th day which denotes the retardation of the external granular cells migration. The embryos and pups of the tramadol group of all studied ages showed the manifestation of degeneration that started from gestational day 16 as evidenced by the disorganization of the purkinje cell plate and the external granular layer. In the pups, the neuronal degeneration increased gradually from the newborn to the adult age. This effect of tramadol was confirmed by the electron microscopic examination of the purkinje and the granule cells that revealed peripheral chromatin condensation, dilated rough endoplasmic reticulum, damaged mitochondria , disrupted organelles, interrupted purkinje cell membrane with disorganization of the spiny appearance, rarified granule cell rosettes and scanty appearance of myelin sheath in the neuropil in between the granule cells. The neuronal degenerative effects of the tramadol also were confirmed by increase in positive iONS immunoreaction of the cytoplasm of the purkinje cells from the newborn age to the adult age. The morphometric study confirmed the degenerative effect of tramadol in all the postnatal studied age groups as evidenced by the decrease in the mean number, surface area and longitudinal diameter of the purkinje cells, the decrease in the mean density of the granule cells, the increase of the mean thickness of the molecular layer in the postnatal 20th day and the adult age, the decrease in the mean thickness of both the purkinje and the internal granular layers in the studied age groups. By examination of the experimental group III, The concomitant use of thyme extract and tramadol showed an improvement in the histological findings as evidenced by normal appearance of the developing cerebellum including germinal triagone, foliation of the cerebellar surface, choroid plexus and stratification of the external granular and purkinje cell layers in the prenatal ages. The postnatal ages revealed normal size and distribution of the basket and satellite cells of the molecular layer. Most of the Purkinje cells were within normal morphology, the internal granular layer showed normal density and organization. The improvement of the histological findings was confirmed by improvement of ultra -structural findings of both the Purkinje and granule cells in form of normal condensation of the chromatin, regularity of the nuclear membrane with variable folding, normal morphology of most of the cytoplasmic and rosettes organelles and organization of the cell membrane with appearance of synaptic spines. Immunohistochemical enhancement also was observed in form of decrease the degree of positive immunoreactivity of the cytoplasm of the Purkinje cells in comparison with the tramadol group. This improvement was ensured by the morphometric findings. Conclusion and Recommendation: *The tramadol intake during pregnancy and lactation exerts a neurotoxic effect on the development and structure of the cerebellar cortex of the embryos and pups. The thyme extract can improve these effects. *Avoid usage of tramadol except in the ultimate necessary cases especially during pregnancy and lactation *Advice taking the thyme extract with the tramadol if prescribed