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Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders

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Abstract

The hippocampus-derived neuroestradiol plays a major role in neuroplasticity, independent of circulating estradiol that originates from gonads. The response of hypothalamus-pituitary regions towards the synthesis of neuroestradiol in the hippocampus is an emerging scientific concept in cognitive neuroscience. Hippocampal plasticity has been proposed to be regulated via neuroblasts, a major cellular determinant of functional neurogenesis in the adult brain. Defects in differentiation, integration and survival of neuroblasts in the hippocampus appear to be an underlying cause of neurocognitive disorders. Gonadotropin receptors and steroidogenic enzymes have been found to be expressed in neuroblasts in the hippocampus of the brain. However, the reciprocal relationship between hippocampal-specific neuroestradiol synthesis along neuroblastosis and response of pituitary based feedback regulation towards regulation of estradiol level in the hippocampus have not completely been ascertained. Therefore, this conceptual article revisits (1) the cellular basis of neuroestradiol synthesis (2) a potential relationship between neuroestradiol synthesis and neuroblastosis in the hippocampus (3) the possible involvement of aberrant neuroestradiol production with mitochondrial dysfunctions and dyslipidemia in menopause and adult-onset neurodegenerative disorders and (4) provides a hypothesis for the possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis in the adult brain. Eventually, understanding the regulation of hippocampal neurogenesis by abnormal levels of neuroestradiol concentration in association with the feedback regulation of HPH axis might provide additional cues to establish a neuroregenerative therapeutic management for mood swings, depression and cognitive decline in menopause and neurocognitive disorders.

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Abbreviations

3β-HSD:

3-Beta-hydroxysteroid dehydrogenase

17β-HSD:

17-Beta-hydroxysteroid dehydrogenase

AD:

Alzheimer’s disease

APOE:

Apolipoprotein E

BDNF:

Brain-derived neurotrophic factor

CaMKII:

Ca2+/Calmodulin-dependent protein kinase II

CREB:

cAMP response element binding protein

ERK:

Extracellular signal regulated kinase

ERα:

Estrogen receptor-alpha

ERβ:

Estrogen receptor-beta

FSH:

Follicle stimulating hormone

GABA:

Gamma-aminobutyric acid

GnRH:

Gonadotropin releasing hormone

HD:

Huntington’s disease

HPG:

Hypothalamic-pituitary–gonadal axis

HPH:

Hypothalamic-pituitary-hippocampal axis

LDL:

Low density lipoproteins

LH:

Luteinizing hormone

LTP:

Long term potentiation

mTOR:

Mechanistic/mammalian target of rapamycin

NSCs:

Neural stem cells

P450scc:

Cholesterol side chain cleavage enzyme

PD:

Parkinson’s disease

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B

StAR:

Steroidogenic acute regulatory protein

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Acknowledgements

MK has been supported by the Faculty Recharge Programme, University Grants Commission (UGC-FRP), New Delhi, India. MK would like to greatly acknowledge a start-up Grant from UGC-FRP, a research Grant (EEQ/2016/000639) and an Early Career Research Award (ECR/2016/000741) from DST-SERB, New Delhi, India. AY has been supported as JRF from DST SERB-EEQ/2016/000639. SAR has been supported as JRF from the DBT, India. CP thank DST-SERB, New Delhi, India for financial support (EMR/2017/003670). MME is highly acknowledging the support given by SQU in the form of an internal Grant (IG/AGR/FOOD/17/02). The authors acknowledge UGC-SAP, DST-FIST and PURSE for the infrastructure of the Department of Animal Science and Department of Biochemistry, Bharathidasan University.

Author information

Author notes

  1. Mahesh Kandasamy and Risna Kanjirassery Radhakrishnan shared first authorship.

Authors and Affiliations

  1. Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    Mahesh Kandasamy, Risna Kanjirassery Radhakrishnan & Ajisha Yesudhas

  2. Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    Mahesh Kandasamy, Risna Kanjirassery Radhakrishnan, Ajisha Yesudhas & Kadalmani Balamuthu

  3. School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    Mahesh Kandasamy, G. P. Poornimai Abirami, Kadalmani Balamuthu, Chidambaram Prahalathan & Muthuswamy Anusuyadevi

  4. Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    Syed Aasish Roshan & Muthuswamy Anusuyadevi

  5. Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620024, India

    Syed Aasish Roshan, Chidambaram Prahalathan & Muthuswamy Anusuyadevi

  6. Department of Bio-Medical Science, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India

    Sellathamby Shanmugaapriya

  7. Department of Integrative Biology, School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    Anbalagan Moorthy

  8. Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman

    Musthafa Mohamed Essa

  9. Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman

    Musthafa Mohamed Essa

  10. Faculty Recharge Programme, University Grants Commission(UGC-FRP), New Delhi, India

    Mahesh Kandasamy

Authors
  1. Mahesh Kandasamy
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  2. Risna Kanjirassery Radhakrishnan
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  3. G. P. Poornimai Abirami
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  4. Syed Aasish Roshan
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  5. Ajisha Yesudhas
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  6. Kadalmani Balamuthu
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  7. Chidambaram Prahalathan
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  8. Sellathamby Shanmugaapriya
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  9. Anbalagan Moorthy
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  10. Musthafa Mohamed Essa
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  11. Muthuswamy Anusuyadevi
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Contributions

MK conceived the present idea, hypothesis and generated the illustration. RKR, PAGP, MK and MA further developed the hypothesis and performed the literature search and made initial draft. MK, RKR, PAGP, SAR, AY, KB, CP, SS, AM, MME, MA contributed to the revision of article, made critical comments and suggestions. All authors discussed the content and contributed to the final manuscript.

Corresponding author

Correspondence to Mahesh Kandasamy.

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Kandasamy, M., Radhakrishnan, R.K., Poornimai Abirami, G.P. et al. Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders. Neurochem Res 44, 1781–1795 (2019). https://doi.org/10.1007/s11064-019-02833-1

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  • DOI: https://doi.org/10.1007/s11064-019-02833-1

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