Chronopharmacology.pptx

Pharmacology-III SEM-VI

1. Chrono pharmacology Vinay Sridhar

2. Rhythmic Events

3. The formal study of biological temporal rhythms, such as daily, weekly, seasonal, and annual rhythms, is called  chronobiology .  To be called circadian, a biological rhythm must meet these three general criteria: The rhythm has an endogenous free-running period that lasts approximately 24 hours The rhythms are entrainable ( i.e.can be reset; eg. jet lag) The rhythms exhibit temperature compensation Chronopharmacology  is the study of how the effects of drugs vary with biological timing and endogenous periodicities.

4. Your boss controls your work… Who controls your body?

5. Who is the master regulator of your time? Suprachiasmatic nucleus (SCN)

6. The "master  clock " that controls  circadian rhythms  consists of a group of nerve cells in the brain called the suprachiasmatic nucleus, or SCN. The SCN contains about 20,000 nerve cells and is located in the hypothalamus, an area of the brain just above where the optic nerves from the eyes cross .

7. SCN SCN PINEAL GLAND MELATONIN MELATONIN MELATONIN MELATONIN PINEAL GLAND

8. Glutamate is the central neurotransmitter released by retinal cells in response to light. Neurons and astrocytes express different types of glutamate receptors ( GluR ). Most of glutamate uptake after its release to extracellular space is mediated by glial transporters (GLAST, GLT-1). In astrocytes, glutamate may be converted to glutamine by glutamine synthetase (GS). In turn, glutamine may be released; neurons are able to uptake it and convert it to glutamate through glutaminase (an enzyme present in both cell types). GS

9. Glutamate-induced calcium influx into SCN neurons represents the first step in the signal transduction pathway leading to entrainment. Voltage-dependent calcium channels (VDCC) are also expressed in SCN neurons and are partially responsible for the increase in [Ca2+] i . The increase in intracellular calcium levels can interact with intracellular stores by activation of IP3 and ryanodine receptors . Moreover, calcium can act directly on posttranscriptional mechanisms leading to changes in clock gene expression and/or activity. Types I and III IP3 receptors are expressed in a circadian fashion, peaking during the early and late subjective night, respectively.

10. CYTOPLASM NUCLEUS CLOCK Bmal1 CLOCK Bmal1 Cry Rev- Erb α Per E-box E-box E-box Cry Rev- Erb α Per Bmal1 Rev- Erb α CKI ε Per CKI ε Per P Cry Per CKI ε Cry Per CKI ε Induction Inhibition SCN neuronal cell RORE

11. Per and Cry genes/proteins Period genes The mammalian period 1 and period 2 genes play key roles in photoentrainment of the circadian clock to light pulses  mPer1 and mPer2 are necessary for the daily resetting of the circadian clock to normal environmental light cues mPer2 knockout mice show increased sensitivity to gamma radiation and tumor development and a significant decrease in apoptosis (non circadian role) Cryptochrome genes Required for sleep homeostasis

12. Afferent inputs and efferent pathways of the SCN RHT: Retinohypothalamic tract, GHT: Geniculohypothalamic tract, OC: Optic chiasm, 3V: Third ventricle, IGL: Intergeniculate leaflet, DM: Dorsomedial SCN, VL: Ventrolateral SCN, NPY: Neuropeptide Y, GABA: Gamma amino butyric acid, PACAP: Pituitary adenylate cyclase-activating polypeptide

13. Preventing dehydration during sleep organum vasculosom lamina terminalis (OVLT) magnocellular neurosecretory cells (MNCs) supraoptic nucleus (SON) paraventricular nucleus (PVN) Vasopressin (VP/ ADH) posterior pituitary (PP) Hypertonic stimulation triggers action potentials in the OVLT and excite MNCs in the SON and PVN in the hypothalamus. The MNCs then go on to produce and release vasopressin into the circulation through the PP, where this hormone promotes water re-absorption. The autonomic nervous system (ANS) also regulates kidney function and prevents diuresis. SCN presynaptically inhibits this sensory input to the MNCs during subjective day. This inhibition is removed during the late sleep phase, resulting in an increase release of vasopressin and water retention in the kidneys

14. Heart attacks  are three times more likely to strike in the  morning  than in the evening.

15. Difficulty waking up? Blame the time keeper within you!

16. Tromsø , which is just north of the Arctic circle, gets about two months of continuous daylight in summer, two months of darkness in winter, and only a few weeks of regular length days around the equinoxes.