Browsing by Author "Derakhshan, Fatemeh"

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    An investigation of the role of insulin deficiency and loss of pi3k-akt signaling in the pathogenesis of the diabetic brain.
    (2012-08-30) Derakhshan, Fatemeh; Toth, Cory
    Type 1 diabetes mellitus (DM) is associated with cognitive dysfunction, cerebral atrophy and white matter abnormalities composing diabetic leukoencephalopathy (DLE). Insulin deficiency contributes to these deficits and is amenable to replacement with intervention using intranasal insulin (I-I) delivery. An important insulin-mediated signalling pathway is propagated through phosphatidylinositol 3-kinase (PI3K) and Akt. We hypothesized that blockade of the PI3K-Akt pathway would prevent I-I’s beneficial effects in mice with DLE, and that this blockade would contribute to development of similar dysfunction in non-diabetic mice. Transgenic mice overexpressing cerebral Akt were expected to be protected from cognitive and white matter changes associated with DM. We interrogated the PI3K-Akt signalling pathway in a mouse model of Streptozotocin- induced type 1 DM over 7 months of life. Diabetic and non-diabetic mice received daily I-I (or intranasal-saline (I-S) for controls) concurrently with intranasal delivery of a PI3K inhibitor (Wortmannin) or an Akt inhibitor (API2). Mice were tested weekly for cognitive function, using a battery of behavioural tests, and endpoint magnetic resonance imaging (MRI). DM mice receiving I-I were protected from cognitive decline, while those mice receiving I-I along with either Wortmannin or API2 were subject to cognitive decline. Interestingly, non-DM mice receiving Wortmannin also developed significant cognitive dysfunction. Akt overexpressing transgenic diabetic mice were protected from cognitive decline. These results suggesting the importance of the PI3K-Akt pathway in DLE in the mouse model of DM.
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    The Role of RVLM and PACAP in Sympathetic Long-Term Facilitation after Exposure to Acute Intermittent Hypoxia Hypercapnia
    (2018-02-21) Derakhshan, Fatemeh; Wilson, Richard J. A.; Duff, Henry J.; Thompson, Roger J.
    Intermittent hypoxia (IHx) and hypercapnia (Hc) episodes are typically a consequence of obstructive sleep apnea (OSA) in adults and immature respiratory control in pre-term infants. IHxHc contributes to immediate and long-term co-morbidities including increased sympathetic output, hypertension, long-term cardiorespiratory instability and stroke. Exposure to an acute phase of IHxHc results in sympathetic long-term facilitation (LTF). Despite intensive investigation, the mechanisms linking IHxHc to increased sympathetic activity and cardiorespiratory instability remain poorly understood. In my thesis project, I explored the role of rostral ventrolateral medulla (RVLM) neurons in development of sympathetic LTF after exposure to IHxHc. I report that PACAP, a highly conserved excitatory neuropeptide, which can function as an "emergency response" co-transmitter in the sympathoadrenal axis, plays a significant role in activating the sympathetic responses to IHxHc, with a prominent role in the RVLM. First, I showed that PACAP plays a critical role during IHx and can save the life of PACAP-KO mice exposed to acute IHx. To the best of our knowledge, PACAP is the first neuropeptide, which is required to survive acute IHx. Second, intermittent stimulation of RVLM area, mirrors the effect of IHxHc with inducing LTF and is sufficient for development of sympathetic LTF, emphasizing on an important role of RVLM neurons in the induction and maintenance of a sympathetic surge after IHxHc. Third, I showed that PACAP action at the RVLM level is necessary for the maintenance of induced sympathetic LTF after exposure to IHxHc. Fourth, I demonstrated that carotid sinus denervation decreases the baseline sympathetic nerve activity but does not suppress the sympathetic nerve response to hypoxia. This finding was explained with the consecutive discovery of spinal cord oxygen sensors. The spinal cord oxygen sensors (SOS) are active over the physiological range and have several qualities of primary oxygen sensors, including a highly-sensitive and rapid physiologic response to changes in oxygen levels. The discovery of PACAP’s role in the maintenance of sympathetic LTF and the existence of SOS introduces a new chapter in current cardiorespiratory research. This new realm has implications for translational studies, such as those investigating sustained sympathetic nerve activity in heart failure,aiming to help patients with chronic obstructive pulmonary disease (COPD), OSA, paroxysmal sympathetic hyperactivity (PSH), and neonates at risks for sudden infant death syndrome (SIDS).