Cerebroprotective and Regenerative Effects of Alkaloid Z77 under Conditions of Brain Ischemia

Abstract

We studied the psychopharmacological effects of atisine-type diterpene alkaloid Z77 in a rat model of cerebral ischemia. Pronounced cerebroprotective effect was found consisting in normalization of the orienting and exploratory activity and conditioned behavior associated with significant correction of morphological changes in the brain. The direct stimulatory effect of Z77 on neural stem cells was shown in vitro.

Mechanisms of Psychopharmacological Effects of Alkaloid Z77 Under Conditions of Brain Ischemia

“…The substance was successively extracted with chloroform, sulfuric acid, ether, and chloroform and chromatographed on deactivated alumina in hexane-acetone system (90→50%). The substance belonging to atisine-type diterpene alkaloids with molecular weight of 357 Da was identifi ed and dissolved in distilled water to a fi nal concentration of 0.00025% [2].…”

“…Experimental ischemia [2] was simulated in rats under ether anesthesia by complete ligation of the left carotid artery and 50% restriction of blood fl ow in the right carotid artery by partial ligation of the artery under the guidance of an electromagnetic fl ow-meter (MFV-1100, Nihon Kohden). To develop various disorders of the psychoneurological status in rats, the surgery was performed in the morning (09.00-10.00) and at night (02.00-03.00).…”

“…On day 3 in 1 h after Z77 administration, the orientation and exploratory behavior was assessed in the open-fi eld test during the fi rst minute and two successive minutes separately and passive avoidance response was conditioned (CPAR). Persistence of the CPAR was tested on experimental day 7 [1,2,15]. In addition, functional asymmetry was evaluated semi-quantitatively by the width of the palpebral fi ssure on the side of complete ligation of the carotid artery as follows: 0 points, the left palpebral fi ssure is completely closed; 1 point, the left palpebral fi ssure is less by one-third compared with the right one; 2 points, the left palpebral fi ssure is less by two-thirds compared with the right one; 3 points, the left palpebral fi ssure is approximately closed; 4 points, the left palpebral fi ssure is completely closed [2].…”

“…In the case of decompensation of adaptation mechanisms, cerebral hypoxia triggers a chain of pathological processes leading to progressive neurological impairment and cognitive disorders including encephalopathy [1,15]. The existing concept of pharmacotherapy of consequences and complications of cerebral ischemia based on the protection or modulation of the functions of mature cells in the nervous tissue that were preserved under pathological conditions is absolutely untenable in some cases [1,2,[4][5][6][7]. In this connection, the development of original cerebroprotective drugs with radically new mechanisms of action is an urgent problem.…”

“…In this connection, the development of original cerebroprotective drugs with radically new mechanisms of action is an urgent problem. In the course of developing "Pharmacological Strategies of Regenerative Medicine" at E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine [1,[8][9][10][11][12][13][14] on the model of cerebral subtotal ischemia, pronounced cerebroprotective effect of alkaloid Z77, which is capable to stimulate the functions of endogenous brain neural stem cells (SC) were revealed [2]. At the same time, the detected psychoneurological events including the normalization of orientation and exploratory behavior of the experimental animals do not allow us to talk unambiguously about cerebroprotective effects of above pharmacological agent.…”