{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:21:17Z","timestamp":1784557277540,"version":"3.55.0"},"reference-count":76,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1,19]]},"abstract":"<jats:p>Thyroid hormones (TH) are vital for brain functions, while TH deficiency, i.e. hypothyroidism, induces neurological impairment in children and adults. Cerebellar neuronal apoptosis and motor deficits are crucial events in hypothyroidism; however, the underlying mechanism is less-known. Using a methimazole-treated hypothyroidism rat model, we investigated cerebellar autophagy, growth factor, and apoptotic mechanisms that participate in motor functions. We first identified that methimazole up-regulated cerebellar autophagy, marked by enhanced LC3B-II, Beclin-1, ATG7, ATG5-12, p-AMPK\u03b1\/AMPK\u03b1, and p62 degradation as well as reduced p-AKT\/AKT, p-mTOR\/mTOR, and p-ULK1\/ULK1 in developing and young adult rats. We probed upstream effectors of this abnormal autophagy and detected a methimazole-induced reduction in cerebellar phospho-epidermal growth factor receptor (p-EGFR)\/EGFR and heparin-binding EGF-like growth factor (HB-EGF). Here, while a thyroxine-induced TH replenishment alleviated autophagy process and restored HB-EGF\/EGFR, HB-EGF treatment regulated AKT-mTOR and autophagy signaling in the cerebellum. Moreover, neurons of the rat cerebellum demonstrated this reduced HB-EGF-dependent increased autophagy in hypothyroidism. We further checked whether the above events were related to cerebellar neuronal apoptosis and motor functions. We detected that comparable to thyroxine, treatment with HB-EGF or autophagy inhibitor, 3-MA, reduced methimazole-induced decrease in Nissl staining and increase in c-Caspase-3 and TUNEL-+ve apoptotic count of cerebellar neurons. Additionally, 3-MA, HB-EGF, and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for the motor performance of rats. Overall, our study enlightens HB-EGF\/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine.<\/jats:p>","DOI":"10.1530\/joe-22-0338","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T08:01:33Z","timestamp":1674115293000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":10,"title":["Hypothyroidism induces motor deficit via altered cerebellar HB-EGF\/EGFR and autophagy"],"prefix":"10.1530","volume":"257","author":[{"given":"Jitendra","family":"Vishwakarma","sequence":"first","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerti","family":"Gupta","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhi","family":"Mishra","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmita","family":"Garg","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafat","family":"Malik","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhirendra","family":"Singh","sequence":"additional","affiliation":[{"name":"Central Pathology Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR\u2013IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0141-7388","authenticated-orcid":true,"given":"Sanghamitra","family":"Bandyopadhyay","sequence":"additional","affiliation":[{"name":"Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"European Journal of Pain","first-page":"1291","article-title":"Experimental hypothyroidism during pregnancy affects nociception and locomotor performance of offspring in rats","volume":"17","author":"Alves","year":"2013","unstructured":"Alves IGda Cruz KMMota CMde Santana DSGaujac DPde Carvalho VCReis LCSluka KAQuintans-Junior LJAntoniolli AR2013Experimental hypothyroidism during pregnancy affects nociception and locomotor performance of offspring in rats. 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